Alzheimer Dementia Case File

Alzheimer Dementia Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 20

A 74-year-old woman was admitted to the hospital for extreme confusion and agitation. She had been doing reasonably well until 1 to 2 weeks prior to admission; however, her family says that her memory has been getting worse over the last 3 years. Initially, she had problems remembering recent events and people’s names and had a tendency to dwell in the past. She has gotten lost several times while driving, most recently in a familiar neighborhood. She has stopped cooking because she can no longer work her electric oven. Sometimes, her words do not make sense. Her social graces have remained preserved, and she is still quite pleasant to be around, although she tends to interact less with her friends. Her family says her mood has been poor lately, with some tearful episodes. She still walks around the block every day, and her basic gait and coordination seem quite normal. Over the last week or so, her condition has acutely worsened. She is easily agitated to the point of aggression. She also appears to see and speak to her mother, who has been dead for many years. According to her family, she has developed frequent urination and incontinence, which is not normal for her. On physical examination, she was found to be inattentive and had difficulty keeping on task. She had numerous paraphasic errors but was otherwise fluent. Her neurologic examination was otherwise unremarkable.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 20:

Alzheimer Dementia                                                    

Summary: A 74-year-old woman was admitted to the hospital for extreme confusion and agitation. She has had short-term memory deficits over the last 3 years including becoming lost several times while driving, most recently in a familiar neighborhood. She now acutely displays confusion, memory loss, hallucinations, and urinary incontinence. She had numerous paraphasic errors but was otherwise fluent. Her neurologic examination was otherwise unremarkable.

• Most likely diagnosis: Underlying dementia, probably Alzheimer disease (AD), with superimposed delirium from a urinary tract infection (UTI).
• Next diagnostic step: Treat UTI with antibiotics, medical evaluation, and observation.
• Next step in therapy: After observation and stabilization, consider treatment of the underlying dementia.

ANALYSIS

Objectives

1. Recognize the differential diagnosis of dementia.
2. Understand the underlying pathophysiology of AD.
3. Appreciate the special susceptibilities of patients with dementia.

Considerations

This case has two main aspects to it: a several-year history of apparent cognitive decline, and a more recent, precipitous decline with agitation and inattention. The insidious onset and gradual progression in an older person is characteristic of degenerative disease (eg, Alzheimer), although other classes of diseases can sometimes mimic this time course. In this patient, there has been decline of cognition with profound deficits of short-term memory. Long-term memory is preserved. Other symptoms include getting lost in familiar areas, suggesting visuospatial deficits, and the use of tools like the oven, which is consistent with apraxia. She had no focal neurologic dysfunction, such as deficits in her cranial nerves, motor, sensation, coordination, gait, and station.

Dementia presents with decline in memory and at least one other cognitive domain that is severe enough to interfere with daily function and independence. The sudden decline and agitation is more consistent with delirium. Dementia needs to be distinguished from delirium, depression, and, more importantly, reversible organic causes of cognitive decline such as drugs or metabolic derangements.

The acute onset of agitation and delirium in this patient is likely caused by a UTI, given her simultaneous development of urinary symptoms (frequency and incontinence). Patients with underlying dementia or other brain disease (eg, stroke and multiple sclerosis [MS]) are particularly sensitive to infections, medication changes, or metabolic abnormalities. Infections are particularly common etiologies of delirium in these patients, though medications and basic laboratory values should also be reviewed.

In this patient, the first order of business is to ensure that she is medically stable. In addition, she should be checked for other causes of delirium, including metabolic and pharmacologic agents as well as vitamin and hormonal deficiencies. Urinalysis and urine culture should be obtained to confirm the diagnosis of UTI, and she should be treated appropriately. She should improve and reach a stable baseline, after which she can be examined more closely as to the nature of her dementia. Cognitive screening tests, such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE), imaging and cerebrospinal fluid (CSF) studies can be performed as indicated by the clinical picture.

If the patient does not have any reversible metabolic causes of cognitive decline, consider the more common dementia syndromes:

1. Alzheimer disease (AD)
2. Lewy body dementia
3. Vascular dementia
4. Parkinson disease (PD) with dementia
5. Frontotemporal dementia (FTD)

In this case, there is neither history of tremor or gait disturbance suggestive of PD nor history of visual hallucinations suggestive of Lewy body dementia. This patient’s history is also not significant for a stepwise deterioration seen with neurologic deficits of stroke, nor is it characterized primarily by personality changes such as disinhibition and impaired judgment seen in FTD. AD is therefore the most probable diagnosis, given the predominant deficits of recent memory and visual-spatial function.

Treatment with an acetylcholinesterase inhibitor such as donepezil, which has been shown to delay symptom progression, would be appropriate at this point. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can also be considered since it has benefit in moderate stages of AD. Dementia is a chronic, progressive disorder; it does not present or change acutely, and there is no need to treat it with the timing and urgency of a cardiac arrest. These patients can be very sensitive to the deleterious effect of medications. Medication should be titrated carefully, and two drugs should never be started at once unless absolutely necessary.

APPROACH TO:

Alzheimer Dementia                                        

DEFINITIONS

DELIRIUM: A transient, usually reversible, cause of cerebral dysfunction that manifests clinically with a wide range of neuropsychiatric abnormalities. The clinical hallmarks are decreased attention span and a waxing and waning type of confusion.

PARAPHASIC ERRORS: The production of unintended syllables, words, or phrases during the effort to speak.

NUCLEUS BASALIS OF MEYNERT: A group of nerve cells that has wide projections to the neocortex and is rich in acetylcholine and choline acetyltransferase.

PSEUDODEMENTIA: A severe form of depression in which cognitive changes mimic those of dementia.

DEMENTIA: Impairment of memory and at least one other cognitive function (eg, language, visual–spatial orientation, judgment) without alteration in consciousness, representing a decline from previous level of ability, and interfering with daily functioning and independent living.

ALZHEIMER DISEASE (AD): The leading cause of dementia, accounting for half of the cases involving elderly individuals, correlating to diffuse cortical atrophy and hippocampal atrophy with ventricular enlargement. The pathologic changes in the brains of AD patients include neurofibrillary tangles with a deposition of abnormal amyloid in the brain.

VASCULAR DEMENTIA (MULTI-INFARCT DEMENTIA): Dementia in the setting of cerebrovascular disease, occurring after multiple cerebral infarctions, whether large or small (lacunar).

APPROACH TO:

Dementia

Dementias can be characterized and categorized in a number of ways. One way is cortical versus subcortical. Cortical dementias involve direct damage to and atrophy of various areas of cerebral cortex. See Table 20–1 for a summary of the main cortical dementias. Cortical dementias tend to have involvement of cognitive functions while basic neurologic function is preserved. Language can be affected, but speech articulation is generally not.

Cortical dementias can also be subdivided based on which lobes of the brain these primarily affect. Cortical dementia affecting the frontal and temporal lobes is typified by FTD. Damage to the frontal cortex produces problems with behavior, attention, and executive dysfunction. Patients can lose their social graces early while memory and intellectual functions can be relatively preserved. Given the role Broca area and related frontal structures play in expressive speech, FTD patients can also present with a nonfluent aphasia, sometimes termed primary progressive aphasia. Semantic aphasia, a problem with word-finding and paraphasias, caused by damage to Wernicke area in the anterior temporal lobe, can result from the temporal involvement in FTD. This is termed semantic dementia. Though the temporal lobe is also the site of the hippocampus, FTD relatively preserves this structure and patients do not have prominent memory deficits.

AD, in contrast to FTD, classically affects the parietal and temporal lobes, sparing the frontal lobe until late in the disease. AD almost invariably shows early involvement of recent memory, with hippocampal atrophy often visible on imaging. Given the parietal involvement, visuospatial skills, calculations, and orientation are usually affected. Patients often forget how to operate common household tools, such as remote controls or vacuum cleaners, due to apraxia.

Another common cortical (and subcortical) dementia is Lewy body disease (LBD). Though not technically correct, it can be helpful to think of LBD as a combination of Alzheimer and PD. These patients frequently have the amnesia and parietal symptoms of AD along with parkinsonism that can be indistinguishable from PD. LBD is the only cortical dementia that commonly affects the occipital lobe. Atrophy of the occipital cortex can be a strong imaging finding in LBD, and this pathology is associated with visual hallucinations, the other classic symptom of the disorder.

In contrast to cortical dementias, subcortical dementia tends to be characterized by attention and processing speed deficiencies, with preservation of core cognitive processes. Neuropsychological testing can show a wide range of deficits but, given enough time and repetition, the patient is often able to complete most tasks. The damage is to the axons or the basal ganglia rather than the neuron cell bodies of the cortex. These disorders can be degenerative, like PD, but can also be the result of fixed injuries, like multi-infarct dementia. Table 20–2 details the salient features of some classic subcortical dementias.

HAART, highly active antiretroviral therapy.

DIFFERENTIAL DIAGNOSIS

If cognitive decline occurs with prominent mood disturbance, then one consideration is depression or pseudodementia. It is often difficult to distinguish which occurred first, as many elderly patients with cognitive decline and declining level of independent functioning suffer from a reactive depression. History from involved family members of the onset of symptoms, or history of prior depression or other psychiatric illness can help establish the diagnosis, and an empiric trial of antidepressants can be considered.

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 known cardiovascular disease or atrial fibrillation, then multi-infarct dementia is the most likely diagnosis. This type of vascular dementia is a common cause of dementia in the United States, comprising 10% to 20% of dementia. Other patients with cerebrovascular disease, especially as a result of long-standing hypertension, can develop diffuse subcortical white matter changes seen on imaging and an insidious rather than sudden stepwise decline in cognitive function. This condition is often referred to as Binswanger disease.

Other common causes of dementia include cognitive decline caused by long-standing alcoholism or by dementia associated with parkinsonism, such as Lewy body dementia and dementia associated with PD. Both of these underlying conditions are readily discovered by the appropriate associated medical history.

Less common causes of dementia include medical conditions such as Wernicke encephalopathy as a result of thiamine (vitamin B1) deficiency, vitamin B12 deficiency caused by pernicious anemia, untreated hypothyroidism, or chronic infections such as HIV dementia or neurosyphilis. A variety of primary central nervous system (CNS) diseases can lead to dementia including Huntington disease, MS, neoplastic diseases such as primary or metastatic brain tumors (although they are much more likely to produce seizures or focal deficits rather than dementia), or leptomeningeal spread of various cancers. Normal pressure hydrocephalus is a potentially reversible form of dementia where the cerebral ventricles slowly enlarge as a result of disturbances to CSF reabsorption. The classic triad is dementia, gait disturbance, and urinary or bowel incontinence. Relief of hydrocephalus through placement of a ventriculoperitoneal shunt can reverse the cognitive decline.

ALZHEIMER DISEASE

AD is a degenerative disorder first identified by Alois Alzheimer, who described the clinical presentation and the characteristic histologic changes, consisting of amyloid plaques and neurofibrillary tangles (Figure 20–1). The amyloid plaques stain positively with antibodies to amyloid precursor protein. AD can be caused by a variety of factors. In 90% of AD, the cause is unknown, while about 10% of cases are associated with known mutations in the amyloid precursor protein as well as two homologous proteins, presenilin-1 and presenilin-2, that tend to present with early-onset disease.

In the past, AD was considered presenile dementia with onset younger than 65 years; however, all age presentations are now considered as dementia of the Alzheimer type. Interference with metabolism of amyloid precursor protein is considered a relevant step in the pathophysiology of AD, sporadic or famililal.

Figure 20–1. Photomicrograph of Alzheimer amyloid plaque and neurofibrillary tangle. (Reproduced, with permission, from Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005:901.)

The diagnosis of AD is made clinically and should be suspected in an older adult with progressive decline in memory and at least one other cognitive domain, causing impaired functioning. Biomarkers and imaging studies serve mainly to exclude other diagnoses. Several biomarker studies have demonstrated that CSF amyloid beta 1–42 is decreased, whereas tau protein is increased in AD. This finding is diagnostically specific but not very sensitive. Apolipoprotein protein E (APO-E) is involved in cholesterol metabolism and plays a role in amyloid metabolism. There are three main haplotypes for this protein, and APO-E e4 is a risk factor for AD whereas e2 is protective. It is possible to order an APO-E genotype from commercial laboratories. It is important to note, however, that the presence APO-E e4 is only a risk factor and is not diagnostic of AD. Imaging studies typically show cortical atrophy, especially the parietal and temporal cortices, with hippocampal atrophy. As a correlate, functional imaging studies show hypometabolism in the temporal and parietal cortices (Figure 20–2). Pathology studies reveal particular degeneration of the cholinergic cells that project to the cortex from the basal forebrain, particularly the nucleus basalis of Meynert. The main approach to enhancing cognition in patients with AD is by trying to enhance cholinergic function by the administration of inhibitors of acetylcholinesterase that penetrate the CNS. One of the consequences of cholinergic loss is also extreme sensitivity to the deleterious effects of anticholinergic medications.

For patients with AD, the average life expectancy after diagnosis is 7 to 10 years. The clinical course is characterized by the progressive decline of cognitive functions (memory, orientation, attention, and concentration) and the development of psychological and behavioral symptoms (wandering, aggression, anxiety, depression, and psychosis). Patients with AD often have olfactory impairment. 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.

Figure 20–2. A. Axial T1-weighted magnetic resonance images of AD patient showing bilateral hippocampal atrophy and generalized atrophy. B. Positron emission tomographic scan with decreased activity in the parietal lobes bilaterally. (Courtesy of TF Budinger, University of California, Berkeley. In: Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:2399.)

Three agents are currently available that inhibit central acetylcholinesterase: donepezil, rivastigmine, and galantamine. All three of these medications have been shown to slow the rate of AD progression. Antagonists to NMDA glutamate receptors, such as memantine, also seem to reduce the rate of decline.

Symptomatic treatments of various psychiatric sequelae can also be very helpful in any dementia. Antipsychotics, such as quetiapine, can be used to treat hallucinations, delusions, or aggression. Other issues patients can develop include wakefulness, wandering, incontinence, and depression. A structured environment, with predictability, and judicious use of pharmacotherapy, such as selective serotonin reuptake inhibitors (SSRIs) for depression are helpful. The primary caregiver is often overwhelmed and needs support. The Alzheimer Association is a national organization developed to give support to family members and can be contacted through www.alz.org.

COMPREHENSION QUESTIONS

20.1 The drugs donepezil, rivastigmine, and galantamine are used in AD to try to raise the availability of which transmitter in the brain?

A. Dopamine

B. Norepinephrine

C. Glutamate

D. Acetylcholine

20.2 Abnormal processing of which of these proteins is felt to be particularly important in the pathophysiology of AD?

A. Acetylcholinesterase

B. Alpha-synuclein

C. Huntingtin

D. Amyloid precursor protein

E. Gamma aminobutyric acid (GABA)

20.3 Which one of these abnormalities on the neurologic examination would be unusual in a patient with mild AD?

A. Problems drawing a clock

B. Impaired sense of smell

C. Hyperreflexia with positive Babinski signs

D. Impaired short-term memory

ANSWERS

20.1 D. There is evidence for both acetylcholine (ACh) and glutamine as important in the development of AD. ACh is essential for the processing of memory and learning and is decreased in concentration and function in patients with AD. The agents donepezil, rivastigmine, and galantamine all inhibit acetylcholinesterase and hopefully result in elevated availability of acetylcholine in the cerebral cortex.

20.2 D. There are abnormalities of amyloid precursor protein deposition. CSF levels demonstrated in AD and mutations in the protein have been shown to cause the clinical disorder. Amyloid precursor proteins are found in the synapses of neurons and are thought to be responsible for forming and repairing synapses; abnormal forms of these proteins may lead to neuronal destruction and dementia.

20.3 C. Hyperreflexia is unusual in AD patients. Impaired olfaction is the only neurologic abnormality typically found, except those on MMSE testing.

    CLINICAL PEARLS    

▶ AD is a cortical dementia with insidious onset and gradual progression. In its early stages, affected patients have a normal neurologic examination except for the mental status examination and olfactory testing. ▶ AD is associated with neurofibrillary tangles with deposition of abnormal amyloid plaques in the brain. ▶ Patients with AD are unusually sensitive to deleterious effects of anticholinergic medications. ▶ Acetylcholinesterase inhibitors have been shown to improve cognition and behavior in patients with AD. ▶ AD is the most common type of dementia, followed by Lewy body dementia. ▶ Depression and reversible causes of dementia should be considered in the evaluation of a patient with memory loss and functional decline.

REFERENCES

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Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387-403. 

Borson S, Raskind MA. Clinical features and pharmacologic treatment of behavioral symptoms of Alzheimer’s disease. Neurology. 1997;48(5 suppl 6):S17-S24. 

Galasko D. The diagnostic evaluation of a patient with dementia. Continuum (Minneap Minn). 2013;19(2 Dementia):397-410. 

Jackson JC, Gordon SM, Hart RP, et al. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol Rev. 2004;14:87-98. 

Lyketsos CG, Lee HB. Diagnosis and treatment of depression in Alzheimer’s disease. A practical update for the clinician. Dement Geriatr Cogn Disord. 2004;17:55-64. 

Muller-Thomsen T, Arlt S, Mann U, et al. Detecting depression in Alzheimer’s disease: evaluation of four different scales. Arch Clin Neuropsychol. 2005;20:271-276.

Sperling R, Johnson K. Biomarkers of Alzheimer disease: current and future applications to diagnostic criteria. Continuum (Minneap Minn). 2013;19(2 Dementia):325-338. 

van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry. 2005;76(suppl 5):v2-v7.

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