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1
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2
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- Identify those at risk
- Treat Early!!
- Question of how aggressively to treat and at what stage
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3
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4
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- Advanced Age
- Half of those >85; 1/10 of those >65
- Female Sex
- “Mild Cognitive Impairment”
- APOE4
- Family History
- Low Education, less imaginative, constricted
- ?Race
- Homocysteine
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5
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6
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- 2011: first baby boomers turn 65
- 18% of population by 2025
- 85+ now 4 million, 8.5 million by 2030
- 50% of Alz pts are at home, 50% in care
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7
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8
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9
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- Greater recent memory impairment than expected for age
- No dysfunction in other Cognitive Spheres
- “Benign forgetfulness of Aging” vs. Alzheimer precurser
- Ideal population for early intervention
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10
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11
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12
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13
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14
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15
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- Risk of Conversion to Alzheimer’s is about 10-15% per year
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16
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17
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18
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- Diffusely projecting area: Nucleus Basalis of Meynert
- Layers I and II major cholinergic cortical innervation
- Amygdala and hippocampus lgest innervation
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19
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- Correlation with Dementia and markers of ACh metabolism:
- CAT: choline acetyl transferase
- AChE: acetylcholinesterase (breaks down ACh)
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20
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- Formation: ChAT and Acetyl-CoA
- Degradation: AchE and Butyryl-cholinesterase
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21
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- Role is minor in normal brain
- Proportionate activity increases in Alzheimer brain
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22
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- Patients on AChE inhibitors had a slower rate of progression than
placebo treated patients
- Raises the issue of possible biological effect of these agents to slow
progression of disease
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23
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- Intervene Early
- Mild Cognitive Impairment??
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24
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25
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26
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- Exelon Approved in April 2000 for treatment of mild to moderate
Alzheimer's disease.
- Benefits: Improved activities of
daily living, including eating, dressing, and household chores. Reduce
behavioral symptoms, such as delusions and agitation. Improved cognitive
function Reduced use of psychotropic medications
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27
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- Shown to improve: Global function, behavior, and Cognition
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28
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- Dose: titrate dosage to achieve optimal effect. Usual dose: 6 to 12
mg/day given BID. Start 1.5 mg bid, increase by 3 mg every 2
weeks. Available in capsule doses of 1.5, 3, 4.5, 6 mg.
- Half life: 2 hours Few interactions with other drugs Side effects: No
hepatotoxicity GI disturbances, occur mainly during dose adjustment.
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29
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- Temporarily inactivates Cholinesterase by forming a Covalent Bond
- 3 mg bid decreases AChE in CSF by 46%
- 6mg bid decreases AChE by 62%
- Duration of signif inhibition lasts up to 6 hours.
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30
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- 56.2% of patients failing Aricept responded to Exelon
- 382 AD patients
- Cibic, MMSE, Activities of Daily Living Scale
- Auriacombe,S et al. Current Research And Opinions 18:(3) 129-38, 2002
(Study Sponsored by Novartis)
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31
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- 18% Men, 26% Women at Max dose
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32
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33
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- CIBIC-Plus: 1-7
- Clinician’s interview-based impression of change with caregiver input
- 1=marked improvement, 4=nc, 7=marked worsening
- ADAS-Cog:0-70
- Higher scores=greater cognitive impairment
- Mild to moderate=15-25
- 6-12 points/yr average deterioration
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34
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35
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- Indicated for mild to moderate
Alzheimer's dementia
- More selective for acetylcholinesterase, the cholinesterase common in
the brain, believed to account for the low incidence of GI side effects
- 5 mg qd for 4 to 6 wk, if tolerate increase to 10 mg qd
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36
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- Pharmacology: Half life:
72-hour Steady states are achieved in 15 days. 94% protein-bound metabolized
by the hepatic P450 enzyme system, but few drug interactions have been
identified. Adverse effect: nausea, vomiting, gastrointestinal
cramping, diarrhea and muscle cramping. Does not have hepatoxicity.
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37
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- Start at 4 mg BID (8 mg/day) for
at least 4 weeks, then 8 mg bid Available in 4 mg, 8 mg, and 12 mg
tablets Most frequent adverse events that occurred with placebo, REMINYL
16 mg/day, and REMINYL 24 mg/day, respectively, were nausea (5%, 13%,
17%), vomiting (1%, 6%, 10%), diarrhea (6%, 12%, 6%), anorexia (3%, 7%,
9%), and weight decrease (1%, 5%, 5%).
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38
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- Average approx. 4 pts on ADAS-Cog Scores
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39
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- Common snowdrop (Galanthus nivalis)
- Binds AChE
- Modulator of Nicotinic Receptors
- ?Enhanced Sexual Fxn
- Mythology
- Iliad, Circe, Atropine, Jimsonweed
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40
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41
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42
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- Vitamin E and Selegeline or donepezil
- Estrogens
- NSAIDs
- B12,B6,Folate (homocysteine)
- Statins
- “Anti-oxidants”
- Valproate ?”Neuroprotective”
- IPA (Indole-3-Propionic Acid) anti-oxidant
- Idebenone?? Analog of CoQ10, anti-oxidant
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43
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44
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45
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- Eight years
- RR= 1.4 for each increase of 1 SD in the log-transformed homocysteine
value either at base line or eight years earlier
- RR of Alzheimer's disease was 1.8 per increase of 1 SD at base line
- RR=1.6 per increase of 1 SD eight years before base line.
- Plasma homocysteine level greater than 14 µmol per liter doubled the
risk of Alzheimer's disease.
- Seshadri et al. N Engl J Med 346:476-483 February 14, 2002
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46
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- Does this mean that lowering H. levels will prevent A’s Disease?
- No one knows
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47
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- 50 Mg pyridoxine
- Up to 1 mg. of Folate
- 500 mcg of B12
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48
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- Preliminary study at Alzheimer congress finds 39% lower risk of in
Alzheimer family members who use statins
- New studies underway
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49
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- 2/3 of Alzheimer Patients are women
- Onset After Menopause
- May increase cholinergic transmission
- Neurotrophic effects
- Anti-amyloidogenic properties
- Association with Neurotrophins
- Regulates synapse formation in hippocampus
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50
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- 3 studies in Neurology 2000;54 show no effect in women already Diagnosed
- Baltimore Long. Study “After adjusting for education, the relative risk
for AD in ERT users as compared with nonusers was 0.46”
- Tang MX et al. Effect of oestrogen during menopause on risk and age at
onset of Alzheimer's disease. Lancet 1996;348:429-432
- Jury Still Out
- Prospective treatment trials
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51
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- NEJM 344:1242-1244 April 19, 2001 Number 16 Richard Mayeux
- Neurology 2000;54:2035-2037 Marder and Sano
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52
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- Inflammation is part of Aβ Accumulation
- Longitudinal Studies show dose related effect of NSAID’s
- Nature Nov. 8, 2001 NSAID’s
directly decrease deposition of Aβ42
- ASA,Celebrex, Naprosyn – no effect
- Others at very high doses decreased production in cells up to 80%
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53
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- Relative risk of Alzheimer's disease of 0.50 among regular users of
NSAIDs, as compared with nonusers
- Stewart et al Neurology 1997;48:626-632
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54
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- Prospective, population-based cohort study of 6989 subjects 55 years of
age or older who were free of dementia at base line.
- Relative risk of Alzheimer's disease was 0.95 in subjects with short-term use of
NSAIDs
- RR= 0.83 with intermediate-term use
- RR= 0.20 with long-term use.
- Risk did not vary according to age
- Use of NSAIDs was not associated with a reduction in the risk of
vascular dementia.
- Bas A. in 't Veld, N Engl J Med 2001; 345:1515-1521, Nov 22, 2001
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55
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- Inflammation is part of Aβ Accumulation
- Longitudinal Studies show dose related effect of NSAID’s
- Nature Nov. 8, 2001 NSAID’s
directly decrease deposition of Aβ42
- ASA,Celebrex, Naprosyn – no effect
- Others at very high doses decreased production in cells up to 80%
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56
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- 2000 Units of Vitamin E and 10 mg. Selegiline
- S. -4 month delay in disease progression e.g. to NH placement
- E. 6 month delay in Disease progression
- No difference on cognitive scores
- Combined treatment did slightly worse than either treatment alone
- Sano et al. N Engl J Med 1997;336:1216-1222
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57
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- RR=.82 per 1SD diff in Vit E or C intake in Rotterdam study
- Englehart et al JAMA 287:3223 (2002)
- Protective effect of Vitamin E seen in questionnaire in E4 negative
group
- Morris et al JAMA 287:3230 (2002)
- Weak effect relating to diet not use of supplements
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58
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- 1 year
- 120 mg.
- 2.4% decrease in Alzheimer’s disease Assessment scale Cognitive subscale
- Very little other evidence
- Le Bars PL et al.JAMA 1997;278:1327-1332
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59
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- 200+ Normals MMSE>26
- 6 wks
- Neuropsych measures
- No Significant effect
- Solomon et al JAMA. 2002;288:835-840
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60
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Notes
