ALZHEIMER DISEASE

ALZHEIMER DISEASE - Jill A.Grimes, MD
BASICS
DESCRIPTION
• Most common cause of dementia in the elderly.
• Degenerative neurologic disease characterized by progressive cognitive and behavioral impairment, usually occurring >65 years of age.
• Diagnosis of exclusion; cost in US >$110 billion/year.
• Usual course: Progressive and chronic
• System(s) Affected: Nervous
• Synonym(s): Presenile dementia; Senile dementia of the Alzheimer type
ALERT
Geriatric Considerations
The US Preventive Services Task Force states evidence is lacking to recommend for or against routine screening for dementia in elderly patients without complaints of memory loss (5).
GENERAL PREVENTION
• Studies of NSAIDs, prednisone, estrogen, and vitamin E have not been shown to delay Alzheimer disease (1,2)[A].
• HRT is not recommended (6)[A].
• Intellectual challenge (puzzles) and regular physical exercise may offer preventive benefit.
EPIDEMIOLOGY
• Predominant age: >60
• Predominant sex: Female > Male (slightly)
Incidence
40% of those >85 are affected, which is 1,100/100,000 people.
RISK FACTORS
• Aging
• Low education level
• Down syndrome
• Positive family history
• Inheritance of the E4 allele of apolipoprotein E gene on chromosome 19 (E4 is a much less of a risk factor for African Americans and Hispanics)
• Smoking (2-4-fold increase)
Genetics
Positive family history in 50% of the cases, but 90% of AD cases are sporadic.
ETIOLOGY
• Unknown, but toxic -amyloid deposits in neuritic plaques and arterial walls appear critical to pathogenesis.
• -Amyloid precursor gene localized to chromosome 21
ASSOCIATED CONDITIONS
• Down syndrome
• Depression


DIAGNOSIS
SIGNS AND SYMPTOMS
• No focal neurologic signs
• Short term memory loss
• Acalculia (e.g., cannot balance check book)
• Agnosia: Inability to recognize objects
• Apraxia: Inability to carry out movements
• Confabulation
• Delusions
• Impaired abstraction
• Decreased attention to hygiene
• Visuospatial distortion
• Late signs
- Psychotic features
- Mutism
History
Include family members in interview (helpful in assessment of behavioral changes, patients).
• Progressive memory loss
• Depression
• Apathy
• Anhedonia
• Intellectual decline
• Loss of interest; social withdrawal
• Occupational dysfunction
• Personality change
• Progressive cognitive impairment
• Restlessness
• Sleep disturbances
• Weight loss
• Incontinence
Physical Exam
• Complete neurologic exam to rule out other causes of dementia
• Folstein mini mental status exam
TESTS
• Lumbar puncture
• Neuropsychologic testing (if clinical picture is confusing or to help determine level of independence for skills such as balancing checkbooks, driving, or managing medicines)
Lab
• To help rule out other causes of dementia (3)[C].
• CBC
• Chemistry panel
• TSH
• Folate and B12 levels
• VDRL or RPR
• Sedimentation rate
• HIV antibody (selected cases)
• Family may have genetic testing for E4 allele of apolipoprotein E gene; not recommended.
Imaging
• Controversy exists concerning cerebral imaging (2,3)[C].
• An MRI or CT is needed to rule out other diagnoses, if cognitive decline is recent, there is history of stroke, or focal neurologic signs are present.
• CT/MRI: Moderate cortical atrophy, ventricular enlargement
• MRI: Hippocampal volumetry; positron emission tomography (PET) and single photon emission computed tomography (SPECT) not indicated.
• Medicare pays for PET to distinguish Alzheimer from frontotemporal dementia.
Pathological Findings
• Gross
- Diffuse cerebral atrophy in hippocampus, amygdala, and some subcortical nuclei
• Micro
• Neuritic senile plaques
- Neurofibrillary tangles
- Pyramidal cell loss
- Decreased cholinergic innervation (other neurotransmitters variably decreased)
- Degeneration of locus ceruleus and basal forebrain nuclei of Meynert; amyloid angiopathy
DIFFERENTIAL DIAGNOSIS
• Vascular dementia; multi-infarct dementia
• Lewy body disease
• Dementia associated with Parkinson disease
• Normal pressure hydrocephalus
• Creutzfeldt-Jakob disease
• End-stage multiple sclerosis
• Brain-tumor: Primary or metastatic
• Subdural hematoma
• Progressive multifocal leukoencephalopathy
• Metabolic dementia (hypothyroidism)
• Drug reactions
• Alcoholism and other addictions
• Dementia pugilistica
• Depression
• Toxicity from liver and kidney failure
• Vitamin and other nutritional deficiencies
• Vasculitis
• Neurosyphilis
TREATMENT
GENERAL MEASURES
• Appropriate supportive care
• Outpatient, day care, assisted living, skilled nursing facility
• Optimize treatment of associated comorbidities
• Occupational therapy
• Music therapy
• Analyze environment for safety and security
• Assess needs of spouse/caregiver
• Advance directives planning
Diet
Nutritional supplements in later stages
Activity
• Exercise to reduce restlessness
• Continued cognitive challenge
Complementary and Alternative Medicine
• Randomized trials of Ginkgo biloba have produced conflicting results (1)[A].
• Coenzyme Q10, Huperzine not effective
MEDICATION (DRUGS)
• Memory enhancement
- Anticholinesterase inhibitors (1,2)[A]: Donepezil (Aricept) 5-10 mg/d, rivastigmine (Exelon) 3-6 mg b.i.d., or galantamine (Razadyne) 8-12 mg b.i.d.
- Best in mild to moderate disease (Folstein MMSE scores 10-24); may show small benefit in more severe disease. Drugs may be effective in Lewy body dementia.
- Only 30-40% of the patients will respond, either by modest improvement or slowed decline over 1-2 years. Unlike tacrine, no liver toxicity seen. Most common side effects are gastrointestinal.
First Line
• No specific drug therapy available for halting disease. Clinical studies are ongoing
• Use as few drugs as possible
• No drugs are helpful for wandering, restlessness, uncooperativeness, hoarding, and irritability. Use behavioral techniques and environmental modification (2)[C].
• For depression (occurs in 1/3 of patients), use selective serotonin reuptake inhibitors (SSRIs).
• Insomnia
- Trazodone 25-100 mg at bedtime, zolpidem (Ambien) 5 mg at bedtime, zaleplon (Sonata) 5-10 mg at bedtime, ramelteon (Rozerem) 8 mg at bedtime.
- Avoid diphenhydramine in elderly males, which can cause urinary retention.
• Moderate anxiety/restlessness
- Consider low-dose, short-acting benzodiazepines, buspirone, or SSRIs, but efficacy unproven
• Severe aggressive agitation (especially if psychotic features present)
- Risperidone (Risperdal) 0.25-1.0 mg b.i.d., olanzapine 2.5 mg/d b.i.d.; other newer atypical antipsychotic agents now preferred due to fewer side effects (2)[C].
- Attempt periodic dose reductions or discontinuation, especially in a nursing home patient (see Omnibus Reconciliation Act [OBRA] 1987)
- Anticholinesterase inhibitors also help behavioral symptoms (4,5)[A].
- Carbamazepine (Tegretol) 100 mg b.i.d.-t.i.d., propranolol (Inderal) 10-40 mg b.i.d.-t.i.d., trazodone 200 mg/d, and valproic acid 250-1,500 mg/d (2)[C].
- SSRIs are also being tried
- Memantine (Namenda) (1)[A], 1st of new class of N-methyl-d-aspartate receptor antagonists; can be used as monotherapy or in combination with acetylcholinesterase inhibitors to enhance or preserve memory. Start 5 mg/d, titrating to target dose of 10 mg b.i.d. after 4 weeks. Shows efficacy in severe disease (MMSE 5-14).
• Contraindications
- Avoid anticholinergic drugs, such as tricyclic antidepressants and antihistamines.
- Ginkgo biloba: Avoid anticoagulants and aspirin
• Precautions
- Benzodiazepines may produce paradoxical excitation or daytime drowsiness
- Triazolam (Halcion) can produce confusion, memory loss, and psychotic behavior.
- Atypical antipsychotic agents have been associated with hyperglycemia, ketoacidosis, increased stroke risk, and increased mortality in elders and dementia cases.
- Anticholinesterase inhibitors provide only modest benefit for 1-2 years, after which decline continues at somewhat lesser rate than placebo. NNT is 7. No deterioration over 6-12 months is evidence of efficacy (1,2)[A].
- Significant possible interactions
- Antipsychotics: Lithium may induce extrapyramidal symptoms and disorientation.
- Benzodiazepines may increase serum phenytoin concentration; cimetidine may increase the benzodiazepine concentration.
- Donepezil (Aricept): Use with caution with anticholinergic medication or in patients with sick sinus syndrome or a history of peptic ulcers. Avoid paroxetine (Paxil), which causes increases donepezil levels.
Second Line
Studies reveal conflicting efficacy of selegiline 5 mg b.i.d., vitamin E, 1,000 b.i.d. or NSAIDS in slowing the progression of the disease (1,2)[A].
FOLLOW-UP
DISPOSITION
Issues for Referral
• Visiting nurse
• Social worker
• Physical therapist
• Occupational therapist
• Lawyer (living will, power of attorney)
• Support groups for patient and family
• Assess driving safety
PROGNOSIS
Poor: Average survival is 4-6 years
COMPLICATIONS
• Behavioral
- Hostility, agitation, wandering, uncooperativeness
• Metabolic
- Infection, dehydration, drug toxicity, malnutrition
• Other
- Falls "Sundowning"
- Depression (1/3 of patients)
- Suicide: In early stages, if depressed
PATIENT MONITORING
• As often as necessary to treat poor nutrition, medical complications, provide support for family, assess need for placement
• Serial mental status testing potentially helpful, but bedside tests (MMSE) offer wide variability and lack of sensitivity
• Monitor caregiver burnout
REFERENCES
1. AHRQ report # 97. Pharmacological treatment of dementia. US Department of Health and Human Services, 2004.
2. Clark CM, Karlawish JH. Alzheimer disease: Current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med. 2003;138:400-410.
3. Knopman DS, Boeve BF, Petersen RC. Essentials of the proper diagnosis of MCI, dementia and major subtypes of dementia. Mayo Clinic Proc. 2003;78(10):290-308.
4. Sink KM, Holden KF, Yeffe K. Pharmacological treatment of neuropsychological symptoms of dementia. JAMA. 2005;293:596-608.
5. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: A meta-analysis. JAMA. 2003;289:210-216.
6. Hogervorst E, Yaffe K, Richards M, Huppert F. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database of Systematic Rev. 4, 2006.
MISCELLANEOUS
See also: Alcohol use disorders; Hypothyroidism; Depression