Acquired syndrome of decline in memory and at least one other cognitive domain sufficient to affect daily life in an alert patient

Cognitive defects in at least one:  Aphasia, Apraxia, Agnosia, Disturbances in executive function

Syndrome of acquired impairment of attention, alertness, and perception

Distinguished from dementia by:

- Acute onset

- Marked fluctuations in cognitive impairment over the course of the day

- Disruption in consciousness and attention

- alterations in sleep cycle

- Assessed cognitive function based on exposure to diphenhydramine

- More delirium, inattention, altered consciousness, catheter placement

- 24% of diphenhydramine doses inappropriate

Potentially reversible:

- Alcoholism

- Depression

- Drug toxicity

- Metabolic disorders

- Nutritional deficiencies

- Infection

Irreversible:

- Alzheimer's disease

- Pick's disease

- Diffuse Lewy Body disease

- Vascular Dementia

Non-modifiable:  Age, gender, race, geographic region, family history

Modifiable:  Hypertension, Diabetes, Hyperlipidemia, Tobacco use, Alcohol use, Drug abuse, OC use

Evaluate - History, mental status, physical, and neurologic exams; Hachinski Ischemia Score, Neuroimaging of the brain

Treatment - Treat vascular risk factors, avoid excessive blood pressure lowering

Diagnosis -  Focused history, physical and neurologic exam, lab eval (CBC, Chem-20, TSH, Vitamin B12, Syphilis serology), neuropsychological testing, neuroimaging

Clinical Global Impression of Change (CGIC) - 7 point severity of illness score with 7 being the worst

Clinical Dementia Rating (CDR) - 5 point scale of impairement, higher number means worse impairment

Global Deterioration Scale (GDS) - 7 stage scale with 7 being severe decline

Mini-Mental Status Exam - Evaluates cognition using 30 points, higher scores are less impairment.  Normal rate of decline in AD is 2-3 points per year, less than 23 isn't good. 

Alzheimer's Disease Assesment Scale-Cog (ADAS-Cog) - 11 item scale with 70 points, higher score is greater dysfunction

- Initial disease process causes primary neuronal injury resulting in neuritic plaques and neurofibrillary tangles

- This causes neuronal death through oxidative stress, loss of nerve growth and inflammation.

- Neuronal death causes NT loss in temporal, parietal, and frontal lobes

- This causes mental sx of depression, delusions, hallucinations, aggression, and sleep-wake disturbances

- Inhibits hydrolysis of acetylcholine in synapse

- Supposedly works because cholinergic deficit is most prominent in AD.

- There are multiple NT deficits also present

- Correlation shown between cholinergic dysfunction and cognition

- Palliative behavioral benefits

- DO NOT USE TACRINE! (COGNEX)

- Similar efficacy as Tacrine

- Improved tolerability

- Half-life 50-70 hours

- Diarrhea and syncope are most common ADR's

Intx - Peptic ulcer disease, bradycardia, reversible airway disease

- Metabolized by P450 2D6 and 3A4

- Dosing start at 5mg, can increase to 10mg after 4-6 weeks

- Similar efficacy and tolerability as Aricept

- Half life is 1 hour, renally eliminated

- GI side effects

- Metabolized by esterases rather than hepatiz enzymes, lower drug intx

- Effect lasts 10 hours, pseudo-irreversible CheI

- Dosing is in patch, or BID 6-12mg/day

- Studied in mild-mod. AD

- GI effects in about 6-10%

- Immediate release BID or XL QD

- Dual mech. of action --> reversible comp. CheI that allosterically modulates nicotinic receptors

                                    Donepezil      Rivastigmine    Galantamine

Enzymes inhibited   

    AChE                         Yes                   Yes                 Yes

    BuChE                        No                   Yes                  No

Plasma half-life (hrs)     50-70               1-1.5                 6

Metabolism by P-450
     isoenzymes        Yes                 No                  Yes

Plasma protein binding    »96%          »40%

Dosing                               QD               BID                BID  

Drug      Effective Dose (mg/d)     ADAS-COG  %     Comp. High. Ds. 

Tacrine                  80-160                 1.4-2.2                       28% ( 30wk)

Donepezil                5-10                    2.5-2.9                      75% (24wk)

                                                                                             65% (24wk)

Rivastigmine           6-12                  2.3-3.8                       65% (26wk)

                                                                                             67% (26wk)

Galantamine           16-24                     3.1-3.9                    68%(26wk)

                                                                                              78% (21wk)

Indication - Mild to severe Alzheimer's disease Lewy Body, severe dementia, behavioral complications

Side Effects - Nausea, dyspepsia, diarrhea, as well as bradycardia

Caution - Reactive airway disease, heart block, and active peptic ulcer disease

Starting doses - Donezepil 5mg in morning, titrate to 10mg after 2-4 weeks

Rivastigmine 1.5mg BID, titrate at monthly intervals, goal 6-12mg/day

Assess for efficacy once goal achieved, MMSE and caregiver impression at 4-6 weeks then every 6 months

Drug Profile: Memantine

- Moderate to severe Alzheimer's

- Before, After, or concurrent cholinesterase inhibitors

- Begin titration:  5mg daily x 7 days, increase by 5mg/week over a 3 week period.  Target dose 10mg BID

- Agitation and aggression

- Psychosis

- Disturbed affect/mood

- Withdrawn/passive behavior

- Anxiety

- Sleep disturbances

- Sun-downing

- Wandering

- Vitamin E (alpha-tocopherol) can help with sx, no more than 400 IU/day