Alzheimer Disease/Dementia Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 37
A 68-year-old woman is noted to have memory loss and confusion. Her daughter relates a history of progressive decline in her mother’s cognitive function over the last year. The patient has lived on her own for many years, but recently she has had difficulty taking care of herself. The daughter states that her mother has become withdrawn and has lost interest in her usual activities, such as gardening and reading. The patient was always a fastidious housekeeper; however, recently she has been noted to wear the same clothes for several days, and her house is unkempt and dirty. She seems anxious and confused. She calls her daughter several times a day, worried that the neighbors, who were previously good friends, are now spying on her. She denies bowel or urinary incontinence, and she has had no trouble with headaches or gait instability. Overall, the patient has been very healthy. Her only medication is hydrochlorothiazide for hypertension. She has never smoked cigarettes and rarely drank alcohol. On examination, her vital signs are within normal limits and stable. She is noted to be well developed, but her affect throughout the examination is rather flat. She is oriented to person and place, but she is a little confused regarding the date. Cardiovascular and abdominal examinations are unremarkable. The extremities are without edema, cyanosis, or clubbing. Cranial nerves are intact, and the motor and sensory examinations are within normal limits. Cerebellar examination is unremarkable, and the gait is normal. Mini-Mental State Examination (MMSE) reveals a score of 24 out of 30.
▶ What is the most likely diagnosis?
▶ What are the best next diagnostic steps?
▶ What is the best treatment for the likely condition?
ANSWERS TO CASE 37:
Alzheimer Disease/Dementia
Summary: A 68-year-old woman presents with
- Memory loss, confusion, and fatigue
- Seeming more withdrawn with a flat affect
- Orientation to person and place, but not to time
- Low MMSE score
Most likely diagnosis: Alzheimer dementia.
Next diagnostic steps: Assess for depression and reversible causes of dementia.
Best treatment: Acetylcholinesterase inhibitor.
ANALYSIS
Objectives
- List some of the common causes and evaluation of dementia. (EPA 1, 2)
- Understand the presentation and diagnosis of Alzheimer dementia. (EPA 1, 3)
- Recognize that acetylcholinesterase inhibitors may slow the progression of dementia. (EPA 4)
Considerations
In this elderly patient with slowly progressive decline in memory and cognitive functioning, dementia due to Alzheimer disease (AD) is the most likely diagnosis. As in other cases of major organ system failure (heart and kidney failures), dementia (“brain failure”) necessitates investigation into treatable or reversible causes before assigning a diagnosis such as AD, which is progressive and incurable and has no effective treatment. In most studies, AD accounts for about 70% of dementia, and about 10% to 20% is due to vascular disorders such as stroke. However, alcohol use disorder, Parkinson, hypothyroidism, and less common disorders should still be explored. Also, depressive disorder needs to be further evaluated. Depression is more common in older patients and can mimic cognitive decline.
APPROACH TO:
Dementia
DEFINITIONS
ALZHEIMER DISEASE: Leading cause of dementia, accounting for half of the cases involving elderly individuals, associated with diffuse cortical and hippocampal atrophy with ventricular enlargement. The pathologic changes in the brains of patients with AD include neurofibrillary tangles and deposition of abnormal amyloid in the brain. Risk factors include advanced age, positive family history, and presence of apolipoprotein E4 allele.
DEMENTIA (also called major neurocognitive disorder): Significant cognitive impairment in more than one of the following cognitive domains: learning and memory, language, executive function, complex attention, perceptual-motor function, or social cognition. The impairment represents a decline from previous level of ability, interferes with daily functioning and independent living, and is not occurring exclusively during an episode of delirium.
VASCULAR (MULTI-INFARCT) DEMENTIA: Dementia in the setting of cerebrovascular disease, occurring after multiple cerebral infarctions, whether large or small (lacunar).
CLINICAL APPROACH
Pathophysiology
In assessing the patient with dementia, the clinician should strive to answer three questions: (1) What is the most likely diagnosis? (2) Is there any treatable or reversible condition contributing to the patient’s cognitive decline? (3) What interventions are available to preserve the patient’s level of function and relieve the burden to caregivers?
To answer the first question, the most important investigation is the history of symptoms. If the patient has an acute or subacute onset of confusion or has a fluctuating level of consciousness, the most likely diagnosis is delirium, which can be due to infection, intoxication, adverse medication effects, medication withdrawal, or metabolic derangements such as hyponatremia, hypercalcemia, or hypoglycemia.
Depression and Pseudodementia. If cognitive decline occurs with prominent mood disturbance, then depression or pseudodementia must be considered. Distinguishing which occurred first is often difficult because many elderly patients with cognitive decline and a declining level of independent functioning suffer from a reactive depression. History provided by involved family members regarding the onset of symptoms or history of prior depression or other psychiatric illness may help establish the diagnosis, and an empiric trial of antidepressants may be considered. An MMSE score of 26 or less suggests mild dementia, with declining scores suggesting more severe dementia. However, a patient should also be screened for depression (eg, Patient Health Questionnaire-9 [PHQ-9]) to rule it out before a diagnosis of dementia is established. Cognitive screenings such as the MMSE and Montreal Cognitive Assessment (MoCA) have relatively high sensitivity (75%-92%) and specificity (81%-91%) for dementia and should be used in screening.
Vascular Dementia. If the patient has a history of irregular stepwise decline in functioning—especially if the patient has had apparent stroke symptoms or transient ischemic events or has a known cardiovascular disease or atrial fibrillation—then vascular, or multi-infarct, dementia is the most likely diagnosis. Vascular dementia is the second most common cause of dementia in the United States, comprising 10% to 20% of dementias. Other patients with cerebrovascular disease, especially as a result of long-standing hypertension, may develop diffuse subcortical white matter changes seen on imaging, presenting with an insidious rather than sudden stepwise decline in cognitive function. This condition is often referred to as Binswanger disease or subcortical arteriosclerotic leukoencephalopathy.
Other Causes. Other common causes of dementia include long-standing alcoholism and parkinsonism. Both these conditions may be discovered by the appropriate history or physical findings (eg, resting tremor with bradykinesia and masked faces of parkinsonism). Other dementia syndromes include behavioral changes with intact navigation in frontotemporal dementia or rapid progression of dementia with muscular rigidity and myoclonus in Creutzfeldt-Jakob disease.
Less common causes of dementia include Wernicke encephalopathy caused from thiamine (vitamin B1) deficiency, vitamin B12 deficiency resulting from pernicious anemia, untreated hypothyroidism, or chronic infections such as human immunodeficiency virus (HIV) or neurosyphilis.
Many primary central nervous system (CNS) diseases can lead to dementia or other cognitive dysfunction, including Huntington disease, multiple sclerosis, neoplastic diseases such as primary or metastatic brain tumors (more likely to produce seizures or focal deficits rather than dementia), or leptomeningeal spread of malignancies. Short-term memory loss, as seen in other dementias, seizures, and psychiatric symptoms, can result from paraneoplastic encephalitis mediated by autoantibodies found in the cerebrospinal fluid (CSF) (eg, limbic encephalitis).
Normal-pressure hydrocephalus is a potentially reversible form of dementia in which the cerebral ventricles slowly enlarge as a result of disturbances to cerebral spinal fluid resorption. The classic triad is dementia, gait disturbance, and urinary or bowel incontinence (wacky, wobbly, and wet). Relief of hydrocephalus through placement of a ventriculoperitoneal shunt may reverse the cognitive decline. Descriptions of the primary neurologic diseases associated with cognitive dysfunction are listed in Table 37–1.
Once likely diagnoses have been established by history and physical examination, investigation should be undertaken to look for treatable or reversible causes. The choice of laboratory or imaging tests is not straightforward because of the numerous, yet uncommon, causes of reversible dementia. Tests that may be considered for the evaluation of dementia are listed in Table 37–2. The American Academy of Neurology recommends routine assessment of thyroid function tests, a vitamin B12 level, and a neuroimaging study, either with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain.
Clinical Presentation
For patients with AD, the average life expectancy after diagnosis is 7 to 10 years. The clinical course is characterized by progressive decline of cognitive functions (memory, orientation, attention, and concentration) and the development of psychological and behavioral symptoms (wandering, aggression, anxiety, depression, and psychosis). Table 37–3 outlines the clinical stages of AD.
Treatment
The goals of treatment in AD are to (1) improve cognitive function, (2) reduce behavioral and psychological symptoms, and (3) improve the quality of life. Donepezil, rivastigmine, and galantamine are cholinesterase inhibitors that are effective in improving cognitive function and global clinical state.
Antagonists to N-methyl-D-aspartate (NMDA) receptors, such as memantine, are effective in moderate-to-severe dementia. Antipsychotics such as risperidone can reduce psychotic symptoms and aggression in patients with dementia but must be used with caution. The Beers Criteria list potentially inappropriate medications for older adults that are associated with negative outcomes; this includes medications that could contribute to altered mental status, which could then be confused for or worsen underlying dementia. For this reason, as well as to avoid polypharmacy, routine medication reconciliation should be done by a primary care provider or whenever a patient is admitted to a hospital.
Other issues include wakefulness, night walking and wandering, aggression, incontinence, and depression. A structured environment, with predictability and judicious use of pharmacotherapy, such as a selective serotonin reuptake inhibitor for depression or trazodone for insomnia, is helpful. The primary caregiver is often overwhelmed and may need support. The Alzheimer Association is a national organization developed to give support to family members and can be contacted through its website (https://www.alz.org).
CASE CORRELATION
- See also Case 36 (Transient Ischemic Attack) and Case 38 (Headache/Temporal Arteritis).
COMPREHENSION QUESTIONS
37.1 A 78-year-old woman is being followed in the office for cognitive decline over the past year. The patient’s daughter states that the patient has been forgetting where she is going and has left the stove on for hours. She is otherwise healthy and denies neurologic symptoms. A workup including laboratory work and head imaging has been negative. The patient is diagnosed with early AD. Which of the following agents is most likely to help with the cognitive function?
A. Haloperidol
B. Estrogen replacement therapy
C. Donepezil
D. High-dose vitamin B12 injections
37.2 A 74-year-old man was noted to have excellent cognitive and motor skills 12 months ago. His wife noted that 6 months ago his function deteriorated noticeably of somewhat sudden onset, and he seemed to be at this new baseline until he became worse 2 months ago. Which of the following is most likely to reveal the etiology of his functional decline?
A. HIV antibody test
B. Magnetic resonance imaging of the brain
C. Cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test
D. Serum thyroid-stimulating hormone
37.3 A 55-year-old man is noted by his family members to be forgetful and become disoriented. He has difficulty making it to the bathroom in time and complains of feeling as though “he is walking like he was drunk.” Which of the following therapies is most likely to improve his condition?
A. Intravenous penicillin for 21 days
B. Rivastigmine
C. Treatment with fluoxetine for 9 to 12 months
D. Ventriculoperitoneal shunt
E. Enrollment into Alcoholics Anonymous
37.4 A 68-year-old man is brought into the clinic due to the patient having difficulty with his memory and with cooking for and shopping for himself. His wife passed away 2 years previously. He often becomes confused about where he is and gets lost when he takes a walk in the neighborhood. He is diagnosed with AD. A CT scan of the brain is performed. Which of the following is most likely to be seen on imaging?
A. Chronic subdural hematoma
B. Cortical atrophy with atrophy of medial temporal structures
C. Ventriculomegaly without cortical atrophy
D. Normal cerebral ventricles and normal brain tissue, acetylcholine deficiency
ANSWERS
37.1 C. Cholinesterase inhibitors such as donezepil help with the cognitive function in AD and may slow the progression. Cholinesterase inhibitors are considered first-line therapy. Haloperidol (answer A) is an antipsychotic agent and is used for patients who display psychosis. It is not useful for early AD. Answer B (estrogen replacement therapy) and answer D (vitamin B12 injections) are not effective treatments for AD.
37.2 B. This is a patient who seems to have a more abrupt staggering or stepwise decline in cognitive function rather than the more gradual decline seen in AD. The stepwise decline in function is typical for multi-infarct dementia, diagnosed by viewing multiple areas of the brain infarct. HIV antibody testing (answer A) can suggest HIV dementia or CNS lymphoma, but this patient does not seem to have risk factors for this infection. CSF for syphilis (answer C) and serum thyroid-stimulating hormone for hypothyroidism (answer D) test for conditions that are usually associated with a gradual decline in cognitive function, versus the stepwise and staggering cognitive decline.
37.3 D. The classic triad for normal-pressure hydrocephalus is dementia, incontinence, and gait disturbance; one treatment is shunting the CSF. A favorable response to large volume (30-50 mL) extraction of CSF can predict the usefulness of the shunt. Intravenous penicillin (answer A) is the treatment for neurosyphilis. Rivastigmine (answer B) is a cholinesterase inhibitor and is used for moderate-to-severe AD. Fluoxetine is a selective serotonin reuptake inhibitor used for depressive disorders. Referral to AA (answer E) is not indicated unless medical causes for his condition are ruled out and alcohol abuse disorder is diagnosed.
37.4 B. Alzheimer disease has no pathognomonic structural imaging criteria but may include cortical and mesial temporal atrophy. This is in contrast to normal-pressure hydrocephalus, which shows enlarged brain ventricles without significant brain atrophy (answer C). Functional imaging can detect decreased perfusion and decreased metabolism in the temporal, parietal, and prefrontal cortex in patients with AD. Chronic subdural hematomas (answer A) may be seen in patients who have repeated falls or trauma; this can be due to elder abuse or alcohol abuse. Acetylcholine deficiency without structural problems (answer D) cannot be evaluated on CT imaging since neurotransmitters are not evaluated on this imaging; however, normal neuroimaging may be present with early AD. This patient has moderate-to-severe AD, and there are very likely to be abnormal findings on CT imaging of the head.
CLINICAL PEARLS
▶ Alzheimer disease is the most common type of dementia, followed by multi-infarct (vascular) dementia.
▶ Approximately 5% of people older than 65 years and 20% older than 80 years have some form of dementia.
▶ Depression and reversible causes of dementia should be considered in the evaluation of a patient with memory loss and functional decline.
▶ Cholinesterase inhibitors are effective in improving cognitive function and global clinical state in patients with AD. An NMDA receptor antagonist is added in more advanced disease.
REFERENCES
Geldmacher DS, Whitehouse PJ. Evaluation of dementia. N Engl J Med. 1996;335:330-336.
Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Neurology. 2001;56:1143-1153.
Seeley WW, Miller BL. Alzheimer’s disease and other dementias. In: Jameson JL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2598-2608.
Tsoi KK, Chan JY, Hirai HW, et al. Cognitive tests to detect dementia: a systematic review and meta-analysis. JAMA Intern Med. 2015;175:1450.
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