Alzheimer Disease Case File

Alzheimer Disease Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 45

A 67-year-old woman is brought into the neurology clinic by her husband for increasing episodes of forgetfulness. The husband states that over the last several years she has had difficulty remembering the locations of her belongings, recalling friends’ names, and has even gotten lost several times in their neighborhood where they have lived for the last two decades. The woman suffers from osteoarthritis, but takes only ibuprofen and is otherwise healthy. Based on this presentation, the physician diagnoses the patient with Alzheimer disease.

The patient is alert and oriented only to self and partly to place (can name the state, but cannot recall the city). She is mildly disheveled. A thorough neurological examination reveals no focal deficits; however, the patient at times has difficulty following directions. She scores 12 out of 30 on the mini mental status exam (MMSE). Her copy of the interlocking pentagons is as follows.

The remainder of her physical examination is normal. Routine laboratory tests show mild hyperlipidemia, but her complete blood count, cobalamin, liver enzyme levels, blood cortisol levels, thyroid-stimulating hormone, and rapid plasma reagent are all normal. A head CT reveals diffuse cerebral atrophy with dilation of the perihippocampal fissure. A diagnosis of Alzheimer disease is made. The patient is placed on a combination of medical and behavioral interventions.

• What are the cortical lesions associated with Alzheimer disease?
• What are treatment options for this condition?

ANSWERS TO CASE 45: ALZHEIMER DISEASE

Summary: A 67-year-old otherwise healthy woman with several years of progressive memory loss.

• Cortical lesions of Alzheimer disease: These include neurofibrillary tangles and senile plaques, occurring mainly in the medial temporal lobe.
• Treatment options: Behavioral modification and psychotropic medication seek to mediate the clinical manifestations of Alzheimer disease. Cholinesterase inhibitors attempt to counter the pathophysiology of the cerebral decrease of acetylcholine. N-methyl-D-aspartate antagonists are utilized at the end stages of the disease. Antidepressants help significantly with corresponding mood disorders. Other investigational treatment modalities include estrogen receptor modifiers, anti-inflammatories, free-radical scavengers, and certain antibiotics.

CLINICAL CORRELATION

Alzheimer disease is a progressive neurodegenerative disorder affecting mainly elderly individuals. As the most common cause of dementia, it is a major cause of morbidity and mortality in the United States. It affects both men and women, the majority of whom are more than 60 years old. Initially, short-term memory is affected greater than long-term memory.

As the disease progresses, patients begin to experience behavioral changes, psychiatric symptoms, difficulty with higher cortical function, and decreased abilities to care for activities of daily living. Alzheimer disease is a clinical diagnosis; therefore, it is important to rule out any treatable cause for dementia. There is no cure for Alzheimer disease. Other causes of dementia include vascular, pharmacological, HIV, delirium, dementia with Lewy bodies, multiinfarct, Pick disease, head trauma, Huntington disease, Parkinson disease, normal pressure hydrocephalus, frontotemporal dementia, Lyme disease, neurosyphilis, prion-related diseases, thyroid disease, Wilson disease.

Current treatments look to prevent or slow the progression of the disease, so far with minimal success.

APPROACH TO MEMORY

Objectives

1. Know the terminology of memory.
2. Understand the cerebral circuitry of memory.
3. Understand the amnesic syndromes.

Definitions

Immediate memory: It may be tested by the ability to repeat a short set of numbers or words; may last for seconds.

Declarative short-term (recent) memory: It may contain seven or less pieces of information at one time and is easily disrupted with distraction; may last from seconds to minutes.

Declarative long-term (remote) memory: It includes explicit information about facts; for example, distant personal or public memories, reciting the helping verbs, completing a multiplication table.

Procedural long-term memory: It includes actions that improve with repetition; for example, riding a bicycle, playing a musical instrument, crocheting; unconscious (ie, automatic).

Anterograde amnesia: It is the inability to retain new information through the conversion of short-term memories to long-term memories.

Retrograde amnesia: It is the inability to recall events occurring before the onset of amnesia; may be temporally graded (ie, distant events are easier to recall than more recent ones).

Consolidation: It refers to short-term memory conversion to long-term memory.

Long-term potentiation (LTP): It includes molecular process strengthening groups of repeatedly used synapses.

Hippocampus: It is located in the medial temporal lobe; from the Greek word for seahorse; responsible for memory consolidation.

DISCUSSION

The neurocircuitry of memory includes the medial temporal system (right and left hippocampus, entorhinal cortex) and the medial diencephalic system (mediodorsal nuclei of the thalamus, mamillary bodies, mamillothalamic tracts). Working or short-term declarative memory is stored in the prefrontal cortex. Conversion into long-term declarative memory utilizes both the medial temporal and diencephalic systems. Long-term memories are stored diffusely throughout the cortex, most likely in the areas responsible for the perception of the initial stimulus. The hippocampus does not seem to play a role for short-term memory, procedural memory, or the end storage of memory. The hippocampus is required for declarative memory consolidation. The cerebellum integrates procedural memory, which is then transmitted to the basal ganglia for storage and coordination.

The physiology of the formation of memories most likely involves LTP. LTP may not be sufficient, but it appears to play a significant role. Studies have shown that hippocampal neurons, when regularly stimulated, convert this constant level of presynaptic stimulation into a larger postsynaptic output. The LTP of a particular neuron may vary depending upon anatomic location and age. The specific mechanisms detailing how LTP leads to the formation of memory has yet to be elucidated.

Declarative memory follows a particular pathway through the hippocampus. Important structures to note include the dentate gyrus, CA1, CA2, CA3, subiculum, and the entorhinal cortex (part of the parahippocampal gyrus). A memory begins as stimulus perceived by the sensory cortex. This information is transmitted by neurons of the entorhinal cortex (hippocampus input), which traverse the subiculum and dentate gyrus (perforant path) to synapse in the dentate gyrus. The “memory” then travels to CA3 (mossy fibers), then CA1 (Schaffer collaterals), and ends up in the subiculum. The subiculum (hippocampus output) projects axons via the fornix to the hypothalamus and mamillary bodies or returns to the entorhinal cortex. At that point the entorhinal cortex relays the information back to the sensory cortex.

Disruption of this pathway leads to an inability to consolidate new memories, while distant memories remain intact. The most famous clinical example of hippocampus injury is from the patient H.M. On August 25, 1953 H.M. underwent resection of his medial temporal lobes, thought to be the etiology of his intractable epilepsy. This included removal of his hippocampus formation, amygdala, entorhinal and perirhinal cortices. From that date onward, H.M. was no longer able to store new declarative memories to his long-term memory cortex. He also suffered from moderate temporally graded retrograde amnesia. H.M. was able to acquire new motor skills (ie, to form new procedural memories); however, he could not recall that he had learned them. Therefore, H.M. demonstrates the result of bilateral lesions of the medial temporal or medial diencephalic system: anterograde amnesia with temporally graded retrograde amnesia, intact short-term and procedural memory, and intact personal identity.

The most common diseases of the hippocampus include Alzheimer disease and epilepsy. Alzheimer disease severely affects CA1, disrupting memory formation. The hippocampus is also particularly sensitive to global ischemia.

COMPREHENSION QUESTIONS

Refer to the following case scenario to answer questions 45.1-45.2:

A 26-year-old man is brought into your clinic because of anterograde amnesia that he has been experiencing for the past several weeks since he was involved in a motor vehicle accident in which he was ejected from his vehicle, and after which remained in the intensive care unit for several weeks. You perform an MRI, which indicates that he has bilateral damage to his medial temporal lobes in the area of the hippocampus.

[45.1] Which of the following processes is most likely disrupted because of these lesions?

A. Short-term memory

B. Storage of long-term memories

C. Retrieval of long-term memories

D. Storage of procedural memory

[45.2] Which neurophysiologic process is thought to be extremely important in storing new memories?

A. Short-term potentiation

B. Ionotropic neurotransmission

C. Long-term potentiation

D. Metabotropic neurotransmission

[45.3] A 33-year-old woman comes into the physician’s office for follow-up after a relatively severe head injury that she suffered on the job several months ago. Overall she seems to be doing well, but she says she has noticed something kind of weird. Recently she has been trying to learn how to knit to help pass the time since she is still not well enough to return to work, but she is having a lot of trouble doing it. She says she used to be very good with her hands, but that every time she picks up the needles it is like it is the first time she has ever used them. She wants to know if this could be related to her injury. Damage to what structure involved in storing procedural memory would be most likely to cause this problem?

A. Cerebellum

B. Hippocampus

C. Prefrontal cortex

D. Mamillary bodies

Answers

[45.1] B. The function of the hippocampus as it relates to memory is in the role of consolidating long-term memories, or transition from shortterm to long-term memory. Short-term memory involves the prefrontal cortex, and long-term memory seems to be stored diffusely throughout the cortex, but the hippocampus is integral in the transition between the two. Because of the location of the injury in this patient, he can recall long-term memories formed prior to the accident without difficulty, and has a perfectly functional short-term memory. His deficiency comes when he has to store his short-term memories as long-term memories, which he cannot do.

[45.2] C. Long-term potentiation in which a given stimulus causes a postsynaptic neuron to alter the way in which it responds to stimuli for a long time (or permanently) is thought to be very important in the storing of long-term memories. Long-term potentiation involves metabotropic neurotransmission, which alters gene expression in the target cell, but metabotropic neurotransmission is not sufficient alone. The mechanism by which long-term potentiation results in memory storage has not yet been specifically determined.

[45.3] A. The cerebellum is thought to play a very important role in the learning of new procedural memory. The other structure that seems to be highly involved in structural memory formation and retrieval is the basal ganglia. The hippocampus and mamillary bodies are involved in consolidation of declarative memory, and the prefrontal cortex is involved in short-term memory.

NEUROSCIENCE PEARLS ❖ The neurocircuitry of declarative memory includes the medial temporal and diencephalic systems. ❖ The cerebellum and basal ganglia integrate, store, and coordinate procedural memory. ❖ As distant memories are stored diffusely throughout the cortex, disruption of the hippocampal pathway leads to an inability to consolidate new memories, while distant memories remain intact. ❖ LTP plays a significant, but still undefined role in memory formation.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2000. 

Purves D, Augustine GJ, Fitzpatrick D, et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates, Inc.; 2004.

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