Clinical History:

This 68-year-old man was noted by his family to have become forgetful in the months before being seen by his family physician. He was brought to his physician by his son because he had been found wandering in the street and could not find his way home. On physical examination, he was unable to remember any of 3 objects after 3 minutes and, although an avid football fan, he was unable to recount the previous Monday night's game which he had watched with his son. A CT scan was obtained and showed mild cerebral atrophy.

Image 3.1:

This is the gross appearance of the brain from a man who died from the same disease suffered by this patient. Describe the findings.

There is atrophy of the cortex with ex-vacuo dilation of the lateral ventricles. No focal lesions are seen.

Image 3.2:

This is a microscopic section of brain stained with H&E. Describe the abnormalities. Do these changes help make a definitive diagnosis?

The section demonstrates neurofibrillary tangles in the cytoplasm of the neurons. These changes are seen in Alzheimer's disease (AD).

Image 3.3:

This is another microscopic section of brain stained with a silver stain. What is the significance of the this finding? What would you advise the family about this disease?

The number of senile plaques found in the cortex is correlated with the presence of AD. Only a few plaques need to be found in those under the age of 65 to make the diagnosis, while in those aged 75 or 80 many more plaques need to be found in order to make a diagnosis. This suggests that some senile plaques are part of normal aging. Although there are familial cases of AD, most cases are not known to be hereditary.

Answers:

1. What is the apparent diagnosis?

Dementia is the most likely diagnosis from the history, although depression in the elderly and metabolic disorders must be ruled out.

2. What other tests would you order on this man?

Thyroid funtion tests, vitamin B12 level, and serologic test for syphilis (e.g., VDRL) will help rule out more treatable causes of dementia. A toxicology screen will help rule out possible unknown drugs.

3. What are the major causes for this condition?

Alzheimer disease (AD), multi-infarct dementia, hydrocephalus, chronic subdural, and dementia with Lewy bodies (DLB) are major causes for dementia. Pick disease is uncommon. Dementia can be seen late in Parkinson disease. AD is by far the most common cause for dementia.

4. Are there potential therapies for this condition?

Cholinesterase inhibitors, which increase the availability of acetylcholine in central synapses, include the drugs tacrine, donepezil, metrifonate, rivastigmine and galantamine. In addition to an effect on improved cognition and slowing of cognitive decline, they have a positive effect on mood and behavior. The length of the effect is uncertain. The majority of patients with Alzheimer's disease have at least one copy of apolipoprotein E4, and these patients seem to have a greater impairment of presynaptic cholinergic function than patients without the apolipoprotein E4 allele, and this might be expected to reduce their response to treatment.

The drug propentofylline (a xanthine derivative), a neuroprotective glial cell modulator, has been shown to reduce the effects of Alzheimer's disease (AD) and vascular dementia (VaD), by antagonizing glial cell activation and increased production of cytokines, free radicals, and glutamate.

Ginkgo biloba extract (EGb 761) is a plant extract containing two major groups of constituents--flavonoids and terpenoids. EGb 761 has antioxidant and free radical scavenging activities. EGb 761 has shown effectiveness when used for symptomatic treatment of cerebral insufficiency of normal aging or degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease and older non-Alzheimer patients may also respond to treatment with EGb 761, which has a stress reducing effect.

5. Explain the biochemistry and genetics of his disease.

The amyloid beta-protein (Aß) is derived by cleavage of the larger amyloid precursor protein (APP). APP is expressed in all mammals. In humans, the APP gene is on chromosome 21. Mutations in the APP gene have been found in familial cases of AD. Mutations in APP increase production of Aß. There are additional genetic mutations that play a role in development of AD. The epsilon4 allele of apolipoprotein E is a major risk for AD of late onset, particularly if both alleles are epsilon 4. The gene is located on chromosome 19. Over half of AD patients have the epsilon 4 allele. Apo epsilon 4 increases levels of Aß in the brain. Mutations in the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1 have been associated with early onset AD. These mutations increase Aß production.

In AD there are extracellular deposits of Aß. In the more numerous, smaller diffuse plaques this Aß alone is present as filamentous masses. However, the diagnostic neuritic plaques also have dystrophic dilated and tortuous neurites, microglia, and surrounding reactive astrocytes.

Neurofibrillary tangles are composed of the hyperphosphorylated microtubule-associated proteins known as tau.

The Aß may be deposited in cortical vessels, principally small arteries and arterioles, leading to a cerebral amyloid angiopathy. These small vessels are prone to bleed.

Neuritic plaques and neurofibrillary tangles can occur independently of each other. Increased numbers of neuritic plaques for age are diagnostic of AD, but tangles are not diagnostic of AD.

6. The patient's son wants to know what arrangements he should make to care for his father. Does he need to be placed in a care facility, and who makes that decision?



Can a person with dementia have capacity to make decisions regarding their medical care?

Yes, a person in the early stages of AD can certainly make their own medical decisions, including making out advance directives.

Can a person with moderate dementia have capacity?

Maybe...such a person may still be able to make some decisions, such as name a person to have durable power of attorney for healthcare decision making. And, importantly, such a person can still express preferences, which may be worthy of respect, even if that person is too confused to make complex decisions.

Must persons with dementia eventually be placed in a 'home'?

No. There is no 'must' to it, sometimes they can stay in their own homes or a family member's home until they die.

What should be done for a late-stage dementia patient who refuses to eat?

Artificially provided nutrition and hydration are not particularly effective treatments for late-stage AD. These patients will usually die within 6 months, no matter what. With a feeding tube they are simply more likely to require additional interventions with subsequent complications: diapers and/or straight catheters complicated by urinary tract infections, restraints and immobilization that predispose to aspiration pneumonia, and other unhappy things that can actually lead to a quicker death.