Chronic Memory Impairment

Thomas C. Rosenthal

CLINICAL PEARLS

The prevalence of dementia doubles every 5 years over 60 years of age, accounting for half of all skilled nursing facility admissions.
Forgetting what things are used for, becoming unable to understand simple instructions or getting lost in familiar surroundings represent thresholds for the diagnosis of dementia.
Performance of novel tasks recruits larger areas of the frontal lobe and hippocampus than does repetition of activities such as counting.
Using formal inventories such as the Mini-Mental State Examination (MMSE), Pfeiffer Short Portable Mental Status Questionnaire and the clock test to score patients can reveal dementia earlier.
As scores on the MMSE drop below 24, nonroutine functions become impaired.
Alzheimer disease is characterized by gradual loss of memory that is serious enough to interfere with social function.
One secretase subtype cleaves the amyloid precursor proteins to form insoluble β-amyloid, which clings to the cell wall as a barnacle-like plaque and generates an inflammatory response.
β-amyloid plaques activate enzymes that damage intracellular microtubules through hyperphosphorylation of tau protein. The tubules twist into compact neurofibrillary tangles that act like foreign bodies within the cell.
Gene typing is commercially available, but variable expression limits its use as a prognostic indicator.
A computed tomography (CT) scan or a magnetic resonance imaging (MRI) study of the head should be obtained in most patients once during the workup,
particularly if the dementia is associated with rapid onset or focal neurologic signs.
Cholinesterase inhibitors are the principal pharmacologic therapy available today but they have a low therapeutic index and a wide variation of individual response.
Lewy body dementia frequently presents with parkinsonian signs, visual hallucinations, and verbal difficulty.
Vascular dementia is associated with focal neurologic signs and gait instability.
Frontotemporal dementia presents as word-finding problems and loss of social prudence.
Low-pressure hydrocephalus presents with blunting of personality, shuffle gait, and urinary incontinence.
Two thirds of patients have multiple causes for dementia on autopsy.
Trazodone is a commonly used agent for elderly patients requiring nighttime sedation.

TABLE 19.1 THE DIFFERENTIAL DIAGNOSIS OF DEMENTIA

Structural (ICD-9)	Metabolic (ICD-9)	Infectious (ICD-9)
Alzheimer disease (331.0)^a	B₁₂ deficiency (281.0)	Endocarditis (421.0)
Amyotrophic lateral sclerosis (335.20)	Chronic drug/alcohol nutritional abuse (305.00)	Creutzfeldt-Jakob disease (046.1)
Brain trauma (854)	Hyperparathyroidism (252.0)	HIV-related disorders (042)
Brain tumor (191)	Hypothyroidism (244.0)	Neurosyphilis (090)
Cerebellar degeneration (331.9)	Hepatic encephalopathy (572.2)	Tuberculous and fungal meningitis (322.9)
Communicating hydrocephalus (331.0)	Uremic encephalopathy (585)	Viral encephalitis (049.9)
Dementia with depression (290.21)^a	Respiratory encephalopathy (496)	Dementia NOS (290.0)
Huntington disease (333.4)	Pellagra (265.2)
Irradiation to frontal lobes (990)
Lewy body dementia (294.8)^a
Multiple sclerosis (340)
Parkinson disease (332.0)
Pick disease (331.1)^a
Supranuclear palsy (333.0)
Vascular disease (290.4)^a
White matter dementia (349.9)^a
Wilson disease (275.1)
^aSubjects covered in this chapter.
HIV, human immunodeficiency virus; NOS, not otherwise specified.

Dementia is cognitive brain failure. The cognitive deficits are manifested by memory impairment (inability to learn new information) and associated with a disturbance in language (aphasia), impaired motor ability (apraxia), inability to identify objects (agnosia), and/or a disturbance in executive functioning (planning, organizing, sequencing, abstracting). To be classified as dementia these defects must impair social or occupational function and represent a decline from a previous level of functioning. Forty percent of people older than 80 years suffer dementia.

Some decline in recall is a normal part of aging, as is a decline in taste, olfaction, vision, and hearing. Healthy elderly people compensate for forgetfulness by writing reminders, putting everything back in its place, and creating other memory aids. Forgettingwhat things are used for, becoming unable to understand simple instructions, or getting lost in familiar surroundings are often the thresholds for unmasking dementia.

The prevalence of dementia doubles every 5 years after 60 years of age, accounting for half of all skilled nursing facility admissions.¹ Home care for patients with dementia costs $3,000 per year.² Alzheimer disease is the most common cause of dementia in the elderly but it accounts for only 65% of cognitive failure. A number of diseases, listed on Table 19.1, can damage the cerebral cortex and subcortical gray matter, and cause cognitive decline. Optimism for future intervention lies in the plasticity exhibited by the human brain. Today’s treatments supplement brain chemistry; tomorrow’s will protect or rebuild structure. This chapter focuses on the differential diagnosis of dementia leading to appropriate choice of management options for patients at risk for progressive dementia.

NORMAL MEMORY AGING

Memory and cognition are dependent on adequate, responsive growth in brain structure. Positron emission tomography (PET) studies of regional cerebral blood flow in subjects learning new tasks demonstrate that memory and recall require frontal lobe and hippocampal activity. Performing novel tasks recruits larger areas of the frontal lobe and hippocampus than does repetition, as demonstrated by London cab drivers who show enlargement of the hippocampus on magnetic resonance imaging (MRI) during their first year of learning the city’s streets.³ Elderly subjects with mild memory loss and MRI evidence of depleted hippocampal volume are most likely to progress to dementia.

TABLE 19.2 MINI-MENTAL STATE EXAMINATION (TO BE COMPLETED BY A TRAINED CLINICIAN)

PATIENT NAME:_____________ DATE:_________ TIME (24hr):_________
Birthdate (mm): (dd): (yyyy):
Sex: [ ] Male [ ] Female Enter education (years):
Race: [ ] Caucasian [ ] Black [ ] Hispanic [ ] Asian [ ] Other
Orientation Questions: Ask the following questions:
right/wrong
[ ] [ ] 1. What is today’s date?
[ ] [ ] 2. What is the month?
[ ] [ ] 3. What is the year?
[ ] [ ] 4. What day of the week is today?
[ ] [ ] 5. What season is it?			DATE
[ ] [ ] 6. What is the name of this clinic (place)?
[ ] [ ] 7. What floor are we on?
[ ] [ ] 8. What city are we in?
[ ] [ ] 9. What county are we in?
[ ] [ ] 10. What state are we in?			PLACE
IMMEDIATE RECALL: Ask the subject if you may test his/her memory. Then say “ball”, “flag”, “tree” clearly and slowly, about 1 second for each. After you have said all 3 words, ask him/her to repeat them. The first repetition determines the score (0-3), but keep saying them until he/she can repeat all 3, up to 6 tries. If he/she does not eventually learn all 3, recall cannot be meaningfully tested:
[ ] [ ] 11. BALL
[ ] [ ] 12. FLAG
[ ] [ ] 13. TREE	Note # trials:	IMMEDIATE RECALL:
ATTENTION
A) Ask the subject to begin with 100 and count backwards by 7. Stop after 5 subtractions. Score the correct subtractions.
[ ] [ ] 14. “93”
[ ] [ ] 15. “86”
[ ] [ ] 16. “79”
[ ] [ ] 17. “72”
[ ] [ ] 18. “65”	SERIAL 7’s TOTAL:
B) Ask the subject to spell the word “WORLD” backwards. The score is the number of letters in correct position. For example, “DLROW” is 5, “DLORW” is 3, “LROWD” is 0.
[ ] [ ] 19. “D”
[ ] [ ] 20. “L”
[ ] [ ] 21. “R”
[ ] [ ] 22. “O”
[ ] [ ] 23. “W”	“DLROW” TOTAL:	Greater score of A or B:
DELAYED VERBAL RECALL: Ask the subject to recall the 3 words you previously asked him/her to remember.
[ ] [ ] 24. BALL?
[ ] [ ] 25. FLAG?
[ ] [ ] 26. TREE?	DELAYED VERBAL RECALL:
NAMING: Show the subject a wrist watch and ask him/her what it is. Repeat for pencil.
[ ] [ ] 27. WATCH
[ ] [ ] 28. PENCIL
[ ] [ ] 29. REPETITION (Ask patient to repeat items in 24, 25 and 26)
3-STAGE COMMAND: Give the subject a plain piece of paper and say, “Take the paper in your hand, fold it in half, and put it on the floor.”
[ ] [ ] 30. TAKES
[ ] [ ] 31. FOLDS
[ ] [ ] 32. PUTS
READING: Hold up a card reading, “Close your eyes”, so the subject can see it clearly. Ask him/her to read it and do what it says. Score correctly only if the subject actually closes his/her eyes.
[ ] [ ] 33. CLOSES EYES
WRITING: Give subject a piece of paper and ask him/her to write a sentence. It is to be written spontaneously. It must contain a subject and verb and be sensible. Correct grammar and punctuation are not necessary.
[ ] [ ] 34. SENTENCE LANGUAGE:
[ ] [ ] 35. DRAW PENTAGONS
TOTAL MMSE:_______________
(MMSE maximum score = 30; 24-30 normal, depending on age, education, complaints; 20-23 mild; 10-19 moderate; 1-9 severe; 0 profound.)
MEDAFILE.COM
(calculation derived from Ashford et al., 1995; Mendiondo et al., 2000)
(forms are in public domain; HTML scripted by Ashford, JW, copyright 2000)

New memory is associated with an increase in the thousands of dendritic synapses each neuron already projects. Healthy elderly people, especially those with high intellectual achievement, have a greater number of memory dendrites available for alternate pathways and recall. When a processing deficiency arises, their brain networks compensate. The velocity of function is biochemical and under the influence of fatigue, nutrition, and mood.

The ability to memorize decreases with age but other cognitive functions remain relatively intact in the healthy individual. Recall may be more labored and the names of familiar persons may not leap to the lips but they are usually recovered with time. In fact, given time, the intellectual performance of healthy elderly people is usually equivalent to earlier years.

Mild cognitive impairment is common. A quarter of community-based elderly demonstrate abnormal scores on a mental state examination without previous evidence of dementia. Most patients who score 24/30 or better on the Mini-Mental State Examination (MMSE) are able to carry out activities of daily living with acceptable adjustments. Family members may first perceive a disability when the patient fails to appear for appointments arranged over the telephone. Progression of mild cognitive impairment is highly variable, and many patients will not progress. Those most likely to progress are older, suffer coexisting cardiovascular disease, have fewer years of education, are undernourished, or have hippocampal atrophy.

Screening

The U.S. Preventive Services Task Force does not recommend for or against routine screening for dementia in older adults because of insufficient evidence of benefit. Early recognition of dementia will become more important as effective pharmacologic agents become available in the future. At present we must rely on family reports of subtle changes in function or behavior. Six items derived from the MMSE can be used to screen patients. The patient who can recall three items (e.g., ball, flag, tree) in 1 minute and correctly state the day of week, month, and year will likely score 24 or above on the MMSE (sensitivity 88.7; specificity 88).⁴ The MMSE (see Table 19.2), Pfeiffer’s Short Portable Mental Status Questionnaire (see Table 19.3), and the clock-drawing test (see Fig. 19.1) are validated examinations that are generally accepted by patients.⁵, ⁶, ⁷ The clock test is more sensitive than the others but less precise in scoring. (The Original Folstein Mini-Mental State Exam is protected by copyright and available from Psychological Assessment Resources, Inc., 16204 North Florida Avenue, Lutz, Florida 33549, or by calling (800) 331-8378. A modified version is available online at www.medafile.com.)

Adults with mental retardation and other chronic intellectual disabilities live longer and create unique challenges as they age. On an average these patients may experience dementia 10 years earlier than the general population. Several screening tools using informant observation have been developed that can assist in recognizing dementia in this special group of adults.⁸

SYMPTOMS AND SIGNS OF DEMENTIA

The earliest sign of dementia, especially the Alzheimer disease type, may be loss of imagination, emotional lability, and eventual withdrawal as the patient becomes frustrated with the challenge of recalling recent events. The family may notice that the patient forgets phone calls or those present at dinner the previous night. A high functioning person ritualistically replaces keys and writes notes, and when they are forced to forgo a ritual they become anxious. Conversation becomes blunted as abstract thinking wanes. The patient begins to rely on the bank to balance their checkbook, avoiding the embarrassment of disputed arithmetic.

TABLE 19.3 SHORT PORTABLE MENTAL STATUS QUESTIONNAIRE—SPMSQ-PFEIFFER

Instructions: Ask questions 1-10 in this list and record all answers. Ask question 4A only if the patient does not have a telephone. Record the number of errors based on ten questions.

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Instructions for Completion of the Short Portable Mental Status Questionnaire

All responses to be scored as correct must be given by the subject without reference to the calendar, newspaper, birth certificate, or other aids to memory.

Question 1 is to be scored as correct only when the exact month, date, and year are given correctly.

Question 2 is self-explanatory.

Question 3 should be scored as correct if any correct description of the location is given. “My home”, correct name of the town or city of residence, or the name of hospital or institution if the subject is institutionalized are all acceptable.

Question 4 should be scored as correct when the correct telephone number can be verified, or when the subject can repeat the same number at another point in the questioning.

Question 5 is scored as correct when stated age corresponds to the date of birth.

Question 6 is to be scored as correct only when the month, exact date, and year are all given.

Question 7 requires only the last name of the President.

Question 8 requires only the last name of the previous President.

Question 9 does not need to be verified. It is scored as correct if a female first name plus a last name other that subject’s last name is given.

Question 10 requires that the entire series must be performed correctly to be scored as correct. Any error in the series or unwillingness to attempt the series is scored as incorrect.

Scoring of the Short Portable Mental Status Questionnaire

The data suggest that both education and race influence performance on the Mental Status Questionnaire and they must accordingly be taken into account while evaluating the score attained by an individual.

For purposes of scoring, three educational levels have been established:

1. Persons who have had only a grade school education

2. Persons who have had any high school education or who have completed high school

3. Persons who have had any education beyond the high school level, including college, graduate school, or business school.

For white subjects with at least some high school education but not more than high school education, the following criteria have been established:

0-2 errors—Intact intellectual functioning

3-4 errors—Mild intellectual impairment

5-7 errors—Moderate intellectual impairment

8-10 errors—Severe intellectual impairment

Allow one more error if subject has had only a grade school education.

Allow one less error if subject has had education beyond high school.

Allow one more error for black subjects, using identical educational criteria.

From Pfeiffer E. A short portable mental status questionnaire for the assessment of organic brain deficit in elder patients. J Am Geriatric Soc. 1975;23:433-41.

As dementia progresses and scores on the MMSE drop below 24, daily function becomes impaired. The patient may get lost in familiar territory, and wandering may become a problem. Recall of remote events is compromised, but not completely lost. As the MMSE drops below 19, personal hygiene suffers and the anxiety created by confusion may express itself as aggression.

As the MMSE drops below 12, the patient is unable to perform activities of daily living and becomes incontinent, at least intermittently. The patient becomes mute because recall is severely compromised. Walking becomes unbalanced and less spontaneous. Sleep patterns become fragmented and haphazard. Expected sensations of hunger and later thirst seem to fail. Below an MMSE score of 9, a blunted febrile and leukocyte response to infection further complicates diagnosing pneumonia or cystitis.

While this linear depiction of Alzheimer disease progression is overly simplified and individually variable, in the terminal phase Alzheimer disease and other structural dementia look much alike. They are terminal illnesses with predictable patterns and should be managed with the support and attention appropriate to any terminal illness. Seizures, coma, and death are common final pathways, often accompanied by sepsis from pneumonia or urinary tract infection.

Figure 19.1 Clock drawing. Instructions: “Draw a clock with all the numbers on it. Then put hands on the clock to make it read 2:45.”

DIFFERENTIAL DIAGNOSIS

The late stages of dementia are hard to differentiate by clinical examination. The clinician’s challenge is to make the correct diagnosis in the early stages when specific intervention may be possible (Table 19.1 lists conditions associated with dementia in the elderly). Alzheimer disease is characterized by gradual loss of memory. Lewy body dementia frequently presents with parkinsonian signs, and upon questioning many patients describe visual hallucinations. Vascular dementia is associated with focal neurologic signs and falling. Frontotemporal dementia starts earlier, with loss of social prudence. Many, if not most, elderly patients will have a dementia of multiple causes, blurring the diagnostic distinctions.

Causes of delirium are discussed in Chapter 18. Delirium develops rapidly and characteristically impacts the patient’s
attention. The course is fluctuating and usually reversible. Delirium may be because of a systemic medical disease or drugs, and should elicit urgent evaluation and treatment.

TABLE 19.4 BRIEF DEPRESSION SCREEN

Score Interpretation
Over the past 2 weeks, how often have you been bothered by any of the following problems?
1.	Little interest or pleasure in doing things
	0: Not at all
	1: Several days
	2: More than half the days
	3: Nearly every day
2.	Feeling down, depressed, or hopeless
	0: Not at all
	1: Several days
	2: More than half the days
	3: Nearly every day
Score	Probability of Major Depressive Disorder (%)	Probability of Any Depressive Disorder (%)
1	15.4	36.9
2	21.1	48.3
3	38.4	75.0
4	45.5	81.2
5	56.4	84.6
6	78.6	92.9
From Thibault JM, Steiner RW. Efficient identification of adults with depression and dementia. Am Fam Physician. 2004;70(6):1101-1110.

Depression

Patients should be screened for depression, a condition difficult to recognize in a brief visit. A quick and effective way to screen patients is with the two questions in Table 19.4, drawn from the Patient Health Questionnaire-9 (PHQ-9).⁹ If the patient answers yes to either question or scores at risk for depression, another depression scale, such as the PHQ-9 or the Beck Depression Inventory, can be used to confirm the diagnosis. The two-question screen has a sensitivity of 96% but a specificity of only 57%. Specificity is improved to 90% if a more detailed follow-up depression inventory is used (Evidence Level B).9 Treatment includes adjustment of the patient’s environment, exercise, and carefully titrated serotonin reuptake inhibitors. A more complete discussion of the management of depression is available in Chapter 17.

ALZHEIMER DISEASE

CASE ONE

Mr. G. is an 81-year-old retired engineer you have cared for over the past 8 years. His son accompanies him today because they want you to fill out an application for skilled nursing home placement. Two weeks ago they moved Mr. G. to the son’s home because he had gone for a drive and had gotten lost. Mr. G. is talkative, bright, and alert, as he has been at previous visits, but you ask him to perform a clock test and are surprised that he cannot arrange the numbers on the face. He scores 19/30 on the MMSE. You recommend a workup and a trial course of a cholinesterase inhibitor. The family agrees to delay placement for a few weeks. When Mr. G. returns in 4 weeks he has lost 3 pounds but scores 24/30 on the MMSE. The family has returned him to his home but taken away his car. You gradually increase his medication to the maximum tolerable amount. Fourteen months later Mr. G. moves into a nursing facility.

This patient scenario represents an outstanding response. More often patients demonstrate little clinically relevant response or stop drugs due to gastrointestinal side effects. Mr. G. was a “responder.”

Definition

Alzheimer disease is a progressive, inexorable loss of cognitive function associated with a large number of β-amyloid plaques in the cerebral cortex (and subcortical gray matter) and neurofibrillary tangles of tau protein. The diagnosis requires that symptoms be associated with cognitive loss in at least two domains including language, calculations, orientation, or judgment. The impairment must be severe enough to cause disability in social or occupational
function.¹⁰ Attention is preserved until late in the course of the illness. In 1906, Alois Alzheimer, correlated the autopsy findings in a 55-year-old patient with dementia who he had followed up for several years. He described the plaques, stringy tangles, and empty spaces we have come to associate with Alzheimer disease. Table 19.5 compares the common types of dementia with Alzheimer disease.

Figure 19.2 Structural neuronal loss in Alzheimer disease (AD).

Pathophysiology

Most elderly patients will have β-amyloid plaques, but the prevailing theory is that in those patients distinguished by Alzheimer disease a large burden of these plaques acts much like a barnacle, destroying the neuron. β-Amyloid is a breakdown product of a repair protein (amyloid precursor protein) in the cell membranes of neurons. Several enzymes on the cell surface cleave amyloid precursor proteins but one secretase subtype splits it to form insoluble β-amyloid. This sticky protein fragment clings to the cell wall. An inflammatory response is initiated by the release of cytokines and complement, attracting glial cells to form a plaque. Research is in pursuit of drugs to selectively block secretase activity.

TABLE 19.5 COMMON DEMENTIA DIAGNOSES

Dementia Diagnosis (Percentage of Dementia)	Clinical Characteristics	Pathology	Treatment
Alzheimer disease (50%-65%)	Progressive loss of cognitive function expressed as memory loss plus disturbances in aphasia, apraxia, agnosia, or executive functioning	β-Amyloid plaques in cerebral cortex Neurofibrillary tangles consisting of tau protein Decreased dopamine	Nutrition Vitamin E Cholinesterase inhibitors Memantine
Diffuse Lewy body dementia (15%-20%)	Hallucinations Fluctuation Parkinsonism	Cytoplasmic inclusion bodies	Cholinesterase inhibitors Antipsychotics, or anti-parkinsonian medications
Frontotemporal dementia (Pick disease) (15%)	Poor hygiene Disinhibition Inability to refrain from touching	Atrophy of the frontal and temporal lobes	Palliative only
Vascular dementia (10%-20%)	Step deterioration Physical signs of neurologic deficit Evidence of atherosclerosis Frequent falls	Lack of blood supply to the brain related to multiple infarcts	Management of hypertension, hyperlipidemia, carotid disease, arrhythmias, diabetes mellitus, polycythemia, and smoking Antiplatelet agents
White matter dementia (5%)	Mood disorders Apathy Perseveration	A complication of diseases of the myelinated white brain matter	Identify underlying condition

β-Amyloid plaques result in activation of kinase (Cdk5 and Csk-3β) that damages intracellular microtubules through hyperphosphorylation of tau protein, the microtubular skeleton. The tubules twist into dysfunctional filaments that act like foreign bodies within the cell. These neurofibrillary tangles are also pathognomonic for Alzheimer disease.¹¹

It is generally agreed that plaques and tangles alter ionic homeostasis and calcium transport, causing neuronal dysfunction, pruning of dendrites, loss of synapses, decreased neurotransmitter release (especially acetylcholine), and cell death. The load and distribution of plaques formed from β-amyloid correlate directly with the severity and manifestation of Alzheimer disease (see Fig. 19.2).

Incidence and Prevalence

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