DR. Vashisth Das 
Functional classification
Syndrome of progressive dementia, other neurological signs being absent/minimal
a.Diffuse cerebral atrophy
· Alzheimer’s Disease
· Diffuse cerebral cortical atrophy of non-alzheimer type
· Some cases of Lewy body dementia
b.Circumscribed cerebral atrophy
· Pick disease (lobar sclerosis)
· Frontotemporal dementia
· Thalamic degeneration
Syndrome of progressive dementia in combination with other neurological abnormalities
· Huntington’s chorea
· Progressive supranuclear palsy
· Cerebrocerebellar degeneration
· Corticobasal degeneration
· Lewy body disease
· Down’s syndrome with Alzheimer histopathology
Historical aspect 
Dr. Alois Alzheimer
Alzheimer was of German origin who initially excelled as a professor of Psychology in Breslau. Later in Munich his interest in histopathology eventually made him a giant in this area. In 1907, appeared the monumental work on Alzheimer’s Disease for which he will always be remembered . He first described Alzheimer’s Disease in a 51- year old woman in 1907.
Epidemiology
Incidence
3 new cases per 100,00 persons < 60 yrs
125 new cases per 100,000 persons > 60 yrs
Prevalence
300 per 100,000 persons aged 60-69
3200 per 100,000 persons aged 70-79
10,800 per 100,000 persons > 79 yrs
Gender
prevalence rates are 3 times higher in females as compared to males
Pathology
Alzheimer's disease. Axial T1-weighted MR images through the midbrain of a normal 86-year-old athletic individual (A) and a 77-year-old male (B) with Alzheimer's disease. Note that both individuals have prominent sulci and slight dilatation of the lateral ventricles. However, there is a reduction in the volume of the hippocampus of the patient with Alzheimer's disease (arrows) compared with the normal-for-age hippocampus of the older individual. Below, fluorodeoxyglucose positron emission tomographic scans of a normal control (C) and a patient with Alzheimer's disease (D). Note that the patient has decreased activity in the parietal lobes bilaterally (arrows), a typical finding in this condition.
Pathogenesis
Neuronal loss in nucleus basalis of Meynert
Decrease in Ach, choline acetyltransferase and nicotinic cholinergic receptors
Decrease in cerebrocortical levels of Ach as a neurotransmitter
Genetic factors
· Trisomy 21
· Presenilins PS-1 and PS-2
· Apolipoprotein E – ε2, ε3, ε4
Miscellaneous
· Age
· Family history
· Sex
· ‘The Nun Study’
· Others
Clinical Features
Summarized by the 4 A’s
· Amnesia
· Aphasia
· Agnosia
· Apraxia
Diagnosis
Neuroimaging
· CT
· MRI
CSF analysis
EEG
Apo E – ε4 allele
Diagnostic criteria (NINCDS and ADRDA)
1.dementia as defined by clinical examination or the mini mental status examination or the blessed scale examination etc.
2.age of the patient > 40 yrs
3.deficits in 2 or more areas of cognition and progressive worsening of memory and other cognitive functions such as language, perception and motor skills
4.absence of disturbed consciousness
5.exclusion of other brain diseases
Differential diagnosis
· Normal pressure hydrocephalus
· Parkinson’s disease
· Vitamin deficiency
· Brain neoplasms
· Pseudodementia
· Chronic drug intoxication
· Creutzfeld Jacob Disease
· Frontotemporal dementia
· Huntington’s disease
Treatment
PHARMACOLOGICAL TREATMENT OF BEHAVIOR AND MOOD
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ANTIPSYCHOTICS (AKA Neuroleptics) |
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TYPICAL |
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Recommended Uses |
General Cautions |
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Used to control problematic delusions, hallucinations, severe psychomotor agitation, and combativeness. |
Current research suggests that these drugs be avoided, if at all possible. They are associated with significant, often severe, side-effects involving the cholinergic, cardiovascular, and extrapyramidal systems. There is also the inherent risk of developing irreversible tardive dyskinesia which can occur in 50% of elderly after three years of continuous use. |
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Typical Agents |
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Dosage |
Specific Cautions |
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Haloperidol (Haldol), fluphenazine (Prolixin), and thiothixene (Navane) |
Initial dose: 0.25-0.5 mg/day; Max: 3-5 mg/day (usually qhs or bid) |
Anticipated extrapyramidal symptoms. If present, lower the dose or switch to another agent; avoid the use of Cogentin or Artane. |
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Thioridazine (Mellaril), chlorpromazine (Thorazine) |
Initial dose: 10-30 mg/day; Max: 100-300 mg/day (usually in multiple doses) |
Significant hypotension, anticholinergic symptons, and drowsiness limit their usefulness. |
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Trifluoperazine (Stelazine), molindone (Moban), perphenazine (Trilafon), and loxapine (Loxitane) |
2.5-5 mg/day; Max: 10-20 mg/day (qhs or bid) |
Agents with an "in-between" side effect profile. |
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ATYPICAL |
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Recommended Uses |
General Cautions |
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Used to control problematic delusions, hallucinations, severe psychomotor agitation, and combativeness. |
Diminished risk of developing EPS and tardive dyskinesia. They are rapidly becoming the new "standard". |
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Atypical Agents |
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Dosage |
Specific Cautions |
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Clozapine (Clozaril) |
Initial dose: 12.5 mg bid; Max: 75-150 mg (in divided doses) |
Generally not used as a first line agent. 1% risk for agranulocytosis, mandatory weekly blood monitoring. Very anticholinergic. |
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Risperidone (Risperdol) |
Initial dose: 0.5 mg qhs; Max: 2-3 mg/day (usually bid) |
Current research supports its use in low doses. EPS may occur at 2 mg. |
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Olanzapine (Zyprexa) |
Initial dose: 2.5 mg qhs; Max: 10-20 mg/day (usually bid) |
Generally well-tolerated. |
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Quetiapine (Seroquel) |
Initial dose: 12.5 mg bid; Max: 75 mg bid |
More sedating; beware of transient orthostasis. |
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NON-ANTIPSYCHOTICS/ANTICONVULSANTS |
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Recommended Uses |
General Cautions |
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Used to control severe psychomotor agitation, and combativeness. Useful alternatives to antipsychotics for severe agitated, impulsive, repetitive, and combative behaviors. Not useful for delusions or hallucinations. |
See "Specific Cautions" |
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Non- |
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Dosage |
Specific Cautions |
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Trazodone (Desyrel) |
Initial dose: 25 mg/day (qd); Max: 200-400 mg/day (in divided doses) |
Use with caution in patients with PVCs. |
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Buspirone (Buspar) |
Initial dose: 5 mg bid; Max: 20 mg tid |
Useful in mild-moderate agitation only. May take 2-4 weeks to become effective. |
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Carbamazepine (Tegratol) |
Initial dose: 100 mg bid; Titrate to therapeutic blood levels: 4-8 ?g/mL |
Monitor CBC and liver enzymes regularly. Problematic side effects. |
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Valproate (Depakote) |
Initial dose: 125 mg bid; Titrate to therapeutic blood levels: 40-90 ?g/mL |
Generally better tolerated. Monitor liver enzymes; platelets & PT/PTT as indicated. |
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BENZODIAZEPINES |
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Recommended Uses |
General Cautions |
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For short term management of insomnia, anxiety, and agitation. |
Regular use can lead to tolerance, addiction, depression, and cognitive impairments. Paradoxical agitation occurs in about 10%. Infrequent, low doses of short half-life agents are least problematic |
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Agents |
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Dosage |
Specific Cautions |
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Lorazepam (Ativan), oxazepam (Serax), temazepam (Restoril), alprazolam (Xanax), zolpidem tartrate (Ambien), and triazolam (Halcion). |
1/4 to 1/2 of the usual adult dose. |
See "specific cautions" for individual agents in the Physician’s Desk Reference. |
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ANTIDEPRESSANTS |
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Recommended Uses |
General Cautions |
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For treatment of clinically significant depression that presents as a primary or comorbid condition. |
Selection is usually based on previous treatment response, tolerance, and taking advantage of potentially beneficial side effects, e.g. sedation vs. activation. A full therapeutic trial requires at least 4-8 week. As a rule, doses are increased using increments of the "initial" dose every 5-7 days until therapeutic benefits or significant side effects become apparent. After 9 months, reassess need for medications by dose reductions. Discontinuing medication over 10-14 days limits withdrawal symptoms. Note: Depressed patients with psychosis require concomitant antipsychotic treatment. |
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TRICYCLIC ANTIDEPRESSANTS (Norepinephrine reuptake inhibitor) |
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Tricyclic Agents |
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Dosage |
Specific Cautions |
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Doxipen (Sinequan/Adapin) |
Initial dose: 10-25 mg qhs; Max: 150 mg qhs |
Useful for depressed patients with agitation and insomnia; significant hypotensive and anticholinergic effects are limiting. |
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Desipramine (Norpramin/Petrofrane) |
Initial dose: 10-25 mg qam; Max: 150 mg qam |
Tends to be activating. Lower risk for cardiotoxic, hypotensive, and anticholinergic side effects. May cause tachycardia. Blood levels may be helpful. |
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Nortriptyline (Aventil/Pamelor) |
Initial dose: 10 mg qhs; Anticipated dosage range of 10-40 mg (bid) |
Tolerance profile similar to desipramine but tends to be more sedating, may be useful for agitated depression and insomnia. Therapeutic blood level "window": 50-150 ng/ml |
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HETERO- AND NONCYCLIC ANTIDEPRESSANTS |
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Hetero- and Noncyclic Agents |
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Dosage |
Specific Cautions |
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Trazodone (Desyrel) |
Initial dose: 25 mg qhs; Max: 200-400 mg/day (qhs or multiple doses) |
Moderately effective; useful for associated anxiety, agitation, or insomnia. Significant AM orthostatic hypotension. Administer with caution in patients with PVCs. |
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Nefazodone (Serzone) |
Initial dose: 50 mg bid; Max: 150-300 mg bid |
Effective, especially with associated anxiety. Caution: Reduce in half the dose of coadministered Xanax/Halcion. |
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Bupropion (Wellbutrin) |
Initial dose: 37.50 mg qam, then 37.50 to 75 mg q3 days; Max: 150 mg bid |
Activating; possible rapid improvement in energy level. Avoid in agitated patients and those with seizure disorders. To minimize risk of insomnia, give second dose before 3 PM. |
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Mirtazapine (Remeron) |
Initial dose: 7.5 mg qhs; Max: 30 mg qhs |
Potent and well-tolerated. Promotes sleep, appetite, and weight gain. |
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SELECTIVE SEROTONERGIC REUPTAKE INHIBITORS (SSRIs) |
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Recommended Uses |
General Cautions |
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These agents may prolong the half-life of other drugs by inhibiting various P450 isoenzymes. |
As a class, typical side effects can include sweating, tremors, nervousness, insomnia/somnolence, dizziness, and various gastrointestinal and sexual disturbances. |
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SSRI Agents |
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Dosage |
Specific Cautions |
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Fluoxetine (Prozac) |
Initial dose: 10 mg every other AM; Max: 20 mg qam |
Activating. Very long half-life; side effects may not manifest for a couple of weeks. |
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Paroxetine (Paxil) |
Initial dose: 10 mg qd; Max: 40 mg qd (AM or PM) |
Less activating but more anticholinergic. |
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Sertraline (Zoloft) |
Initial dose: 25-50 mg qd; Max: 200 mg qd (AM or PM) |
Best tolerated SSRI; less effect on metabolism of other medication. |
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Fluvoxamine (Luvox) |
Initial dose: 50 mg bid; Max: 150 mg bid |
Caution when using with Xanax or Halcion (reduce in half). |
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Citalopram (Celexa) |
Initial dose 10mg; Max: 30mg/q.d. |
Well tolerated SSRI |
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Venlaflaxine (Effexor) |
Initial dose: 37.5 mg bid; Max: 225 mg/day in divided doses |
Most potent SSRI-plus (also inhibits norepinephrine reuptake) |
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LITHIUM |
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Recommended Uses |
General Cautions |
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Anti-cycling agent that may also be used to augment antidepressant medication. |
The elderly are prone to develop lithium neurotoxicity at higher doses. |
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Agent |
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Dosage |
Specific Cautions |
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Lithium |
Initial dose: 150 mg qd |
Blood levels between 0.2-0.6 meq are generally adequate; usually achieved with 150-300 mg bid. |
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ELECTROCONVULSIVE THERAPY (ECT) |
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Recommended Uses |
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For those at risk of injuring or starving themselves; the severely psychotic; and the antidepressant non-responsive or intolerant may require a course of ECT |
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Drugs are listed from most recent to last, as approved by the FDA.
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DRUG NAME |
MANUFACTURER’S RECOMMENDED DOSAGE |
COMMON SIDE EFFECTS |
POSSIBLE DRUG INTERACTIONS |
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ReminylÒ (galantamine) Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain. |
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Nausea, vomiting, diarrhea, weight loss |
Some antidepressants such as paroxetine, amitriptyline, fluoxetine, fluvoxamine, and other drugs with anticholinergic action may cause retention of excess Reminyl in the body, leading to complications; NSAIDs should be used with caution in combination with this medication.* |
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ExelonÒ (rivastigmine) Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain. |
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Nausea, vomiting, weight loss, upset stomach, muscle weakness |
None observed in laboratory studies, NSAIDs should be used with caution in combination with this medication.* |
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AriceptÒ (donepezil) Prevents the breakdown of acetylcholine in the brain. |
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Nausea, diarrhea, vomiting |
None observed in laboratory studies, but NSAIDs should be used with caution in combination with this medication.* |
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CognexÒ (tacrine) Prevents the breakdown of acetylcholine in the body, not specific to the brain. Note: Cognex is still available but no longer actively marketed by the manufacturer. |
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Nausea, diarrhea, possible liver damage |
NSAIDs should be used with caution in combination with this medication.* |
* Use of cholinesterase inhibitors can increase risk of stomach ulcers, and because prolonged use of non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin or buprofen can also cause stomach ulcers, NSAIDS should be used with caution in combination with these medications.
Future Strategies
· Gingko biloba
· Aβ peptide immunization
· Protease inhibitors
· NSAID’s
Bibliography
· Adams and Victor’s “Principles of Neurology” - 7th edition
· Brain’s Diseases of the Nervous System – 10th edition
· Harrison’s Principles of Internal Medicine – 15th edition
· http://www.alzheimers.org (alzheimer’s disease education and referral centre)
· http://www.nlm.nih.gov/medlineplus/alzheimersdisease (US national institute of health)
a transcript of this presentation can be downloaded from
http://vashisthdas.tripod.com