Chapter 5. Use of the Laboratory in the Diagnostic Workup of Older Adults
© American Psychiatric Publishing
Laboratory testing is an essential component of the psychiatric evaluation of elderly individuals, who often present with comorbid medical illnesses. The laboratory does not replace the clinician; there is no test that is pathognomonic for a primary psychiatric illness. However, laboratory testing does aid in the evaluation of comorbidities that complicate or contribute to a psychiatric diagnosis.
There has been significant growth in the number and quality of diagnostic tools available. Progress in research and technology, particularly in imaging technology and genetic testing, has advanced rapidly over the past decade. Regardless of the tools available, however, we must balance what we can do with what we should do, as guided by our clinical judgment, relative risk to the patient, and cost expenditure. When all risks are considered, the decision to proceed with a test should be based on the clinical presentation and on how the test results may change a treatment plan.
The following discussion of specific diagnostic tests is not an exhaustive review. We focus on tests currently being used or being considered for clinical use. We hope this chapter will assist the clinician in selecting laboratory tests that are appropriate for the individual patient.
Serologic Tests
Basic clinical chemistry and hematologic screens are routine for all hospital admissions and many outpatient evaluations. Although these screens infrequently identify causes of primary psychiatric disorders, they are critical for identifying previously undiagnosed or poorly controlled medical illnesses that may contribute to mental status changes, such as in dementia or delirium. These tests should also be monitored when patients are taking medications that may result in potentially dangerous abnormalities. For most of these tests, the only risks are associated with blood draws, which may result in transient pain, bruising, and occasional bleeding or fainting. These risks are reduced, but not totally eliminated, by skilled phlebotomists.
Hematologic Tests
A complete blood cell count (CBC) is a standard part of any evaluation. It screens for multiple problems, including infections and anemia. It also provides a platelet count, a value important to monitor in psychiatric medications associated with thrombocytopenia, such as divalproex sodium or carbamazepine. This concern is particularly important in elderly patients, because the risk of drug-induced thrombocytopenia may increase with age. Lithium, in contrast, may result in mild leukocytosis. Because of the risk of agranulocytosis, CBC testing is required weekly or biweekly for patients taking clozapine and may be needed more frequently if the patient develops signs of infection. Mirtazapine can also lead to agranulocytosis in rare cases, and although routine CBC monitoring is not indicated, it should be pursued if a patient develops sore throat, fever, stomatitis, or other signs of infection.
Chemistry Tests
Most general chemistry panels have a variety of values that may be helpful in medical evaluations. Blood glucose values may reveal hyperinsulinemia and hypoglycemia, which may produce anxiety and weakness; more commonly these tests show hyperglycemia, which may be associated with diabetes and result in lethargy or, in severe cases, delirium, diabetic coma, or ketoacidosis. This testing is critical for the diagnosis of diabetes, which can be diagnosed with 1) an overnight fasting glucose greater than 126 mg/dL, 2) a random plasma glucose greater than 200 mg/dL with symptoms of diabetes, or 3) an oral glucose tolerance test resulting in a plasma glucose over 200 mg/dL 2 hours after a 75-g glucose load.
Kidney function tests are equally important. Blood urea nitrogen and creatinine will be elevated in kidney failure and in hypovolemic states such as dehydration. These tests also must be performed before initiating lithium therapy because of lithium’s potential for nephrotoxicity.
General chemistry panels also measure serum sodium, potassium, and other electrolytes. Hyponatremia—commonly defined as a serum sodium concentration less than 135 mEq/L—has been reported with selective serotonin reuptake inhibitors (SSRIs), particularly in the elderly. The signs and symptoms of hyponatremia result from neurological dysfunction secondary to cerebral edema. Acute hyponatremia can start with nausea and malaise when the plasma sodium concentration falls below 125–130 mEq/L and progresses rapidly to coma and respiratory arrest if the plasma sodium concentration falls below 115–120 mEq/L. In chronic hyponatremia, the brain cells adapt to the edema, and symptoms are much less severe. Patients may be asymptomatic despite a plasma sodium concentration that is persistently as low as 115–120 mEq/L. When symptoms do occur in individuals with such low sodium concentrations, they are relatively nonspecific (e.g., fatigue, nausea, dizziness, gait disturbances, forgetfulness, confusion, lethargy, muscle cramps). The clinician should be vigilant to this risk in older adults when they begin taking SSRIs. Of all the electrolyte abnormalities, potassium disorders may be the most crucial to identify. These rarely cause psychiatric symptoms but may result in severe cardiac arrhythmias. Although not always included in routine chemistry screens, calcium and magnesium levels are also important to consider, because abnormal levels may result in paranoid ideation or frank psychosis. Any or all of these results may be abnormal in patients undergoing hemodialysis.
Because second-generation antipsychotics can lead to weight gain and diabetes, a set of guidelines has been proposed to screen and monitor patients who are taking these drugs (Table 5–1) (American Diabetes Association et al. 2004). These guidelines should be routinely incorporated into clinical practice by all geropsychiatrists. Additionally, when patients develop abdominal pain while being treated with atypical antipsychotics or valproic acid, their amylase and lipase levels should be checked to rule out pancreatitis. Liver function tests should be monitored periodically in patients taking valproic acid. There have been case reports of both venlafaxine and duloxetine causing elevated hepatic enzymes and even hepatic failure. Liver function tests should be obtained in patients taking these drugs who develop symptoms of liver disease.
Chemistry Tests Guidelines for screening and monitoring of patients taking second-generation antipsychoticsa
Assessment | Frequency |
|---|---|
Personal and family historyb
|
At baseline and annually
|
Weight
|
At baseline, every 4 weeks for 12 weeks, then quarterly
|
Waist circumferencec
|
At baseline and annually
|
Blood pressure
|
At baseline, at 12 weeks, and annually
|
Fasting plasma glucose
|
At baseline, at 12 weeks, and annually
|
Fasting lipid profile
|
At baseline, at 12 weeks, and every 5 years
|
aMore frequent assessments may need to be done based on clinical status.
bPersonal and family history includes obesity, diabetes, dyslipidemia, hypertension, and cardiovascular disease.
cWaist circumference is measured at umbilicus.
| |
Source. American Diabetes Association et al. 2004.
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Serologic Tests for Syphilis
Although syphilis was nearly eliminated in the United States in 2000, the rate of primary and secondary syphilis cases steadily increased between 2001 and 2013, mainly due to higher rates among gay, bisexual, and other men who have sex with men (Centers for Disease Control and Prevention 2014). Men from this demographic group who are infected with HIV and are of lower socioeconomic status are at especially high risk of syphilis infection. According to the American Academy of Neurology’s guidelines for diagnosis of dementia, unless the patient has some specific risk factor (e.g., another sexually transmitted disease) or evidence of prior syphilitic infection or unless the patient resides in one of the few areas in the United States with high numbers of syphilis cases, screening for the disorder in patients with dementia is not justified (Knopman et al. 2001). If a clinician suspects syphilis infection, the Venereal Disease Research Laboratory and the rapid plasmin reagin tests are screening tools for infection with Treponema pallidum, the cause of syphilis. These tests are unfortunately nonspecific; false-positive results may occur in acute infections and chronic illnesses such as systemic lupus erythematosus. More specific tests, the fluorescent treponemal antibody and the microhemagglutination assay for Treponema pallidum, may distinguish false-positive from true-positive results and may aid in diagnosing late syphilis when blood and even cerebrospinal fluid (CSF) reagin tests are negative.
Human Immunodeficiency Virus Testing
According to the Centers for Disease Control and Prevention (2013), HIV infection has become a significant issue in the geriatric population. About 30% of HIV infections occur in individuals ages 50 years and older, and 17% of new HIV diagnoses are made in this age group.
The diagnosis of AIDS in elderly individuals is complicated; like syphilis, AIDS has been described as a “great imitator” because its clinical presentation may mimic that of other diseases (Sabin 1987). AIDS may mimic not only medical illnesses but also neuropsychiatric disorders, because AIDS may result in dementia.
There is no evidence that HIV treatment for elderly AIDS patients should differ from that for younger patients. It is therefore the role of the geriatric psychiatrist to assist the internist by screening for risk factors, such as a history of sexually transmitted diseases, intravenous drug use, risky sexual behavior, or a history of blood transfusions, particularly if they occurred prior to the early 1990s. We recommend HIV testing for individuals who have these risk factors or those who present with atypical neuropsychiatric symptoms. For patients for whom testing is warranted, the psychiatrist will also play an important role in counseling the patients about the reasons behind testing, and then providing further counseling as the test results are reported.
Thyroid Function Tests
To understand the significance of thyroid test results, one must first understand the hormones themselves. Secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) is regulated by pituitary gland secretion of thyroid-stimulating hormone (TSH). TSH secretion, in turn, is controlled through negative feedback by thyroid hormones. Both T4 and T3 are reversibly bound to the plasma protein thyroxine-binding globulin, and only the small unbound fraction exerts its physiological effects.
A serum TSH test is the most frequently used screen for thyroid disease; it is an excellent screening test because of its high negative predictive value (Klee and Hay 1997). However, many medications may result in increased TSH levels (amiodarone, estrogens) or decreased TSH levels (glucocorticoids, phenytoin), and altered TSH levels may also be seen in patients with acute nonthyroidal illness or systemic stress. A physical examination and measurement of T4, T3, and TSH may be required for a definitive diagnosis of thyroid disease (Table 5–2). TSH testing should be done in all older adults presenting with neuropsychiatric symptoms because hypothyroidism may cause symptoms of depression, fatigue, and impaired cognition, and hyperthyroidism can cause symptoms of anxiety or even psychosis. Older women in particular have a high prevalence of hypothyroidism. Patients who are taking lithium should have their TSH level checked every 6 months.
Thyroid Function Tests Patterns of thyroid function tests
TSH | Free T4 | T3 | Suggested diagnosis |
|---|---|---|---|
Normal
|
Normal
|
Normal
|
Euthyroid
|
High
|
Low
|
Low or normal
|
Primary hypothyroidism
|
High
|
Normal
|
Normal
|
Subclinical hypothyroidism
|
Low
|
High or normal
|
High
|
Hyperthyroidism
|
Note. TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine.
| |||
Vitamin B12, Folate, and Homocysteine
Measurement of serum vitamin B12 and folate levels is an integral part of the laboratory evaluation. The prevalence of B12 deficiency increases with age; the deficiency is present in up to 15% of the elderly population. Although macrocytic anemia is a well-known sign of B12 deficiency, it is a later presentation in most cases, with neuropsychiatric symptoms presenting much earlier.
Vitamin B12 and folate deficiencies may result in neuropsychiatric disturbances, including depression, psychosis, or cognitive deficits. In patients with dementia, B12 deficiencies often result in delirium or disorientation. Low levels of these vitamins may also result in visuospatial and word fluency deficits (Robins Wahlin et al. 2001) and even greater behavioral disturbances in patients with Alzheimer’s disease (AD) (Meins et al. 2000).
However, vitamin B12 and folate levels may not tell the entire story; there is also considerable interest in homocysteine. Serum homocysteine levels may serve as a functional indicator of B12 and folate status, because both vitamins are needed to convert homocysteine to methionine in one-carbon metabolism in brain tissue. Hyperhomocysteinemia is prevalent in elderly persons, and high serum levels of homocysteine can be attributed to an inadequate supply of B12 and folate, even in the presence of low normal serum levels (Selhub et al. 2000). High levels of homocysteine have also been associated with increased risk of occlusive vascular disease, thrombosis, and stroke (Boushey et al. 1995). Hyperhomocysteinemia is further associated with cognitive dysfunction (Leblhuber et al. 2000; Selhub et al. 2000), although not all authors have found this association (Ravaglia et al. 2000). In a longitudinal study of 965 older individuals, a lower incidence of AD was noted among those subjects in the highest quartile of total folate intake, after adjustments for age, sex, education, ethnicity, and other comorbidities. Neither vitamin B6 nor vitamin B12 intake was associated with risk of AD (Luchsinger et al. 2007). Results on whether vitamin supplementation to reduce plasma homocysteine levels also leads to improved cognition are mixed, with some studies showing benefit (Durga et al. 2007; Nilsson et al. 2001) and others showing no benefit despite lowered homocysteine levels (McMahon et al. 2006).
Toxicology
When an acute change occurs in an individual’s mental status, an investigation of the cause of the change must include the possible ingestion of a substance. This consideration is particularly important in individuals with a history of substance abuse or with a history of depression for whom there is the risk of medication overdose.
When mental status changes in an individual who is taking medications such as lithium, phenytoin, tricyclic antidepressants (TCAs), or any medication that requires monitoring of blood levels, those levels should be checked. Toxic levels of many pharmacological agents may cause a variety of psychiatric or life-threatening medical conditions. Likewise, levels for common over-the-counter medications such as acetaminophen and salicylates can be tested. Concomitantly, a serum alcohol level should also be drawn. Depending on the individual’s history, even a negative result may be critical if there is the possibility of withdrawal. Finally, urine can be tested for prescription medications, such as benzodiazepines, barbiturates, and opioids, as well as illicit substances, such as cocaine and marijuana. Advanced age does not preclude addiction.
Urinalysis
A urinalysis is an inexpensive, noninvasive test that provides a significant amount of information. It determines the urine’s specific gravity, which may indicate dehydration, and also tests for glucose and ketones, important in the evaluation of diabetic patients. In the elderly population, the most important use of urinalysis may be as a screening tool for urinary tract infections (UTIs). A UTI is suggested when a microscopic examination shows high levels of white blood cells, bacteria, positive leukocyte esterase and nitrite, and possibly red blood cells; high numbers of epithelial cells make the results difficult to interpret, because their presence suggests contamination. A urine culture is a definitive means of diagnosing a UTI and will identify the infecting organism and its susceptibility to antimicrobial treatments. Approximately 20% of admissions from the community to geropsychiatry units may have UTIs, and many cases of UTI result in a delirium that improves with appropriate antibiotic treatment (Levkoff et al. 1991; Manepalli et al. 1990).
Cerebrospinal Fluid Analysis and Plasma Assays for Dementia
Although one of the most common diagnostic uses of CSF analysis is the workup of suspected central nervous system infections (such as meningitis), CSF analysis is now playing an increasingly important role of the assessment of patients with dementia. In patients with AD and mild cognitive impairment (MCI) due to AD, CSF levels of β-amyloid peptide 1–42 are reduced, whereas levels of phosphorylated tau (p-tau) and total tau (t-tau) are increased (Blennow et al. 2010; Hansson et al. 2006). Increased p-tau is more specific for AD than β-amyloid but less sensitive (Hansson et al. 2006; Maddalena et al. 2003). Tau elevations, however, can also be found in other conditions such as frontotemporal lobar degeneration (FTLD) and Parkinson-plus syndromes. Other promising assays for AD include CSF measurement of β-amyloid oligomers and amyloid precursor proteins. The combination of these CSF biomarkers may improve accuracy in the diagnosis of AD. Although CSF biomarkers are not part of the routine dementia workup, they may be considered in special circumstances when clinicians have difficulty distinguishing among various types of dementia and when such biomarker measurements are available. National Institute on Aging–Alzheimer’s Association guidelines for diagnosing AD have also focused on the use of plasma and CSF biomarkers and neuroimaging for the early detection of preclinical AD and MCI due to AD (Jack et al. 2011). Research studies, most notably Alzheimer’s Disease Neuroimaging Initiative 2, are under way to better characterize the utility of these biomarkers in the context of neuropsychological testing and neuroimaging.
A number of assays have been developed for early-onset and rapidly progressive dementias. Two promising assays for FTLD include the measurement of plasma levels of progranulin (PGRN) and transactive response DNA-binding protein of 43 kDa molecular weight (TDP-43). Mutations of PGRN have been associated with FTLD with tau-negative, ubiquitin-positive inclusions (Forman et al. 2006), and lower plasma levels of PGRN are predictive of PGRN mutations in patients with FTLD and asymptomatic family members (Finch et al. 2009). TDP-43 proteinopathy has also been associated with both FLTD and amyotrophic lateral sclerosis, which suggests these are two processes on a disease continuum (Neumann et al. 2006). Elevated levels of TDP-43 in the CSF and plasma are seen in FTLD, amyotrophic lateral sclerosis, and AD; plasma levels of phosphorylated TDP-43 may be more specific for FTLD (Foulds et al. 2009).
Hsich et al. (1996) described an immunoassay for the detection of the 14-3-3 protein in CSF that had a specificity of 99% and a sensitivity of 96% for the diagnosis of Creutzfeldt-Jakob disease (CJD) among patients with dementia. CSF 14-3-3 protein assay has been found to be superior to electroencephalography or magnetic resonance imaging (MRI) in identifying cases of CJD (Poser et al. 1999). However, other acute neurological conditions such as stroke, viral encephalitis, and paraneoplastic neurological disorders can provide false-positive results. Nevertheless, the American Academy of Neurology recommends testing for CSF 14-3-3 protein for confirming or rejecting the diagnosis of CJD in clinically appropriate circumstances (Knopman et al. 2001).
Electrocardiogram
An electrocardiogram (ECG) provides a graphic representation of the heart’s electrical activity, obtained via surface electrodes placed in specific locations on the patient’s chest. This placement makes possible a graph of electrical activity from a variety of spatial perspectives. In psychiatry, the most important roles of the ECG include screening for cardiovascular disease that may preclude the use of specific medications and monitoring for drug-induced electrocardiographic changes either from standard doses or from overdose. Electrocardiographic changes associated with specific psychotropic medications are summarized in Table 5–3.
Electrocardiogram Common electrocardiographic abnormalities associated with psychotropic medications
Medication | Electrocardiographic change |
|---|---|
Antipsychotics (typical or atypical agents)
|
Increased QTc interval
Potential for torsades de pointes
|
β-Blockers
|
Bradycardia
|
Lithium
|
Sick sinus syndrome
Sinoatrial block
|
Tricyclic antidepressants
|
Increased PR, QRS, or QT intervals
Atrioventricular block
|
The TCAs are well known to be cardiotoxic in overdose; even at therapeutic doses, their use is considered unsafe in patients with cardiovascular disease, particularly ischemic disease. Although the most common cardiovascular complication of TCAs is orthostatic hypotension, TCAs have the same pharmacological properties as type IA antiarrhythmics, such as quinidine and procainamide. TCAs slow conduction at the bundle of His; individuals with preexisting bundle branch block who take TCAs are at increased risk for atrioventricular block. Even therapeutic levels are associated with prolonged PR intervals and QRS complexes; these results may be more pronounced in elderly individuals because the incidence and severity of adverse drug reactions increase with age. If TCAs are used, baseline and frequent follow-up ECGs should be obtained.
Lithium may also result in electrocardiographic changes, and ECGs are recommended before starting and regularly while taking lithium. Lithium appears to most affect the sinus node, and even at therapeutic levels it may result in sick sinus syndrome or sinoatrial block, either of which may occur early or later in treatment. At higher levels, there have been reports of sinus arrest and asystole.
Antipsychotics also result in electrocardiographic changes; about 25% of individuals receiving antipsychotics exhibit electrocardiographic abnormalities (Thomas 1994). Although many of these changes have historically been considered benign, there is increased concern that prolongation of the QT interval (when corrected for heart rate, the QTc interval) may contribute to potentially fatal ventricular arrhythmias, particularly torsades de pointes. QTc values are typically around 400 milliseconds in duration; values lower than this are considered normal. Because the greater the duration, the greater the risk of torsades, 500 milliseconds is frequently used as a cutoff. It is important to note that other medications also affect the QTc interval and produce an additive effect when combined with an antipsychotic. This phenomenon may be seen with almost any antipsychotic agent but is most likely to be associated with thioridazine and haloperidol among typical antipsychotics and with ziprasidone among atypical antipsychotics. Unfortunately, there are currently concerns about QTc prolongation for all atypical antipsychotic agents.
In 2011, the U.S. Food and Drug Administration (FDA) posted a black box warning recommending against dosages of citalopram over 40 mg/day (20 mg/day in patients ages 60 years and older) because of the risk of QTc prolongation and torsades de points. Further studies have had mixed findings; one study questioned whether there was truly a concern with citalopram (Zivin et al. 2013), whereas another study found modest prolongation not only for citalopram but also for escitalopram and amitriptyline (Castro et al. 2013). Further studies will be needed to address the effects of citalopram and other antidepressants on QTc and torsades de pointes. Until more data are available, physicians should continue to discuss the black box warning with their patients before the initiation of citalopram (and possibly escitalopram).
Notably, there are various methodologies of how to correctly calculate the QTc interval for an individual. For each person, the QT decreases as the heart rate increases. The formula for correction is QT/RRc, in which RR = the RR interval and c = the correction factor. According to the FDA, the most accurate proposed method is to calculate this correction factor for an individual based on 50–100 pretreatment ECGs, and this is the recommended approach for Phase I ECG trials (U.S. Food and Drug Administration 2005). Other methodologies for calculation include the population-based approaches, such as the Bazett, Fridericia, linear regression, and nonlinear regression techniques. The Bazett QT correction formula is most frequently used in clinical practice and in the medical literature, but clinicians should be aware that this type of correction tends to be inaccurate at the extreme ranges (both elevated and low).
Routine ECGs for all patients receiving antipsychotics are not currently recommended, but it is wise to be prudent. A careful history for cardiac illness, family history, or syncope should be obtained for all patients. ECGs should be considered more carefully when patients have other risk factors, such as heart failure, bradycardia, electrolyte imbalance (particularly with low levels of potassium and magnesium), female sex, old age, hepatic or renal impairment, and slow metabolizer status. ECG and/or electrolytes should be performed in patients with risk factors, and citalopram should be discontinued if the QTc persistently exceeds 500 milliseconds.
With few exceptions, an ECG should always be obtained in cases of potential medication overdose, even when the medication used is not associated with arrhythmias. ECGs are important because some medications may affect heart rhythm in overdose when they would not do so at usual doses. Also, suicidal patients often do not report all the medications that they have used to overdose; suicide attempts may be impulsive, and patients who have an altered mental status may not be able to provide a complete report.
Imaging Studies
Plain film radiographs remain an integral piece of the diagnostic imaging performed in geriatric psychiatry. Such techniques are most commonly used to detect lung pathology that may contribute to mental status changes or to detect bone fractures. Plain film radiographs are critical for individuals who have both severe dementia and either a recent history of falls or newly developed limb immobility.
A number of more recently developed imaging techniques have greatly enhanced diagnostic abilities. These techniques are costly, so they should not be used without a good rationale that includes why they are needed and how the specific findings may affect a patient’s treatment plan. The following discussion focuses on two commonly used structural imaging techniques: computed tomography (CT) and MRI. Because these techniques are also discussed in other chapters of this book, we focus on the scientific basis behind these tools and provide information to support their clinical use, particularly in brain imaging, and to facilitate providing informed consent.
Other imaging techniques such as single-photon emission computed tomography (SPECT) and functional MRI are used mostly in research and have limited clinical use, and therefore are not discussed here. Amyloid imaging agents involving positron emission tomography (PET) are also used primarily in research, but because of the number of ongoing clinical research trials being done to establish their utility, a brief discussion is included later.
Computed Tomography
Computed tomography is a general term for several radiographic techniques that result in the computer-assisted generation of a series of images showing slices of an organ or body region, such as the brain or abdomen. The CT scanner uses a small X-ray device that rotates around the body region of interest in a fixed plane; these signals are sent to a computer that produces the corresponding cross-sectional slice for that plane. The computer can create sections in axial, coronal, and sagittal alignments. More recent advances in software and display systems have led to many useful clinical applications, including virtual CT colonoscopy or angiography.
When used to examine brain structure, CT can allow for the ready identification of many structures, although it does have limitations. By measuring differences in density, it can distinguish among CSF, blood, bone, gray matter, and white matter. CT is particularly useful for demonstrating bone abnormalities (such as skull fractures), areas of hemorrhage (such as a subdural hematoma), and the mass effect from various lesions. It can also display atrophy or ventricular enlargement. However, CT is not very useful for visualizing posterior fossa or brain stem structures because of surrounding bone.
A typical concern of patients is radiation exposure. CT scans require the use of a limited amount of radiation; any given CT procedure results in a radiation exposure, but that exposure is well below governmental recommendations for individuals who work around radiation. However, these recommendations do not consider multiple CT scans (thus multiple radiation exposures) or CT studies that overlap scanned regions, a technique that increases the radiation dose. CT imaging should be used when appropriate, but other assessment techniques that may result in lower radiation exposure should also be considered.
Whereas CT scanners rely on radiation, in MRI, the scanner creates a magnetic field that is 3,000–25,000 times the strength of the earth’s natural magnetic field. The underlying principle behind MRI is that the nuclei of identifiable endogenous isotopes (such as hydrogen or phosphorous) behave like tiny spinning magnets. Strong magnetic fields alter this behavior, and an MRI scanner can identify the resultant change.
When a patient is put into the strong, static magnetic field generated by the MRI scanner, his or her nuclei align parallel to the field. Because the nuclei are also spinning, they wobble randomly around the field; different molecules can be identified because their nuclei wobble at different frequencies. A second, oscillating magnetic field is then applied at a right angle to the first. This field affects only the nuclei that are in resonance with it—that is, the nuclei that wobble at the field’s frequency. This second field forces those resonant nuclei to wobble in unison. When this field is deactivated, the nuclei return to their original positions, and the synchronized movement creates a voltage that can be measured and displayed. Measurements taken at various times during the procedure produce the different magnetic resonance images.
MRI has advantages and disadvantages when compared with CT. MRI produces higher-resolution images and can obtain good detail in regions (such as the posterior fossa) that are poorly visualized on CT. Additionally, no radiation is involved in MRI. Unfortunately, the procedure is more grueling than CT because the patient must remain motionless for a longer period of time in a smaller, enclosed space. This may be difficult for individuals who are claustrophobic. Additionally, the magnetic device must be housed in an area devoid of iron, and staff and patients must not carry or wear certain metals or have them embedded in their bodies. Moreover, MRI tends to be more costly than CT imaging in most institutions.
In the psychiatric workup of a geriatric patient (Table 5–4), MRI should be considered when the clinician suspects small lesions in regions difficult to visualize—for example, to obtain evidence of midbrain hemorrhage in a patient with suspected Wernicke’s encephalopathy, or to confirm a suspected pituitary tumor in an individual with hyperprolactinemia, which may be seen in association with risperidone and other high-potency antipsychotic agents. Hyperprolactinemia carries the risks of osteopenia, sexual dysfunction, amenorrhea, breast enlargement, and possibly cardiac disease and breast cancer. Switching from high-potency to low-potency antipsychotic drugs such as quetiapine or aripiprazole has been shown not only to normalize prolactin but also in some instances to reverse menstrual function or other symptoms (Shim et al. 2007). MRI can also easily identify vascular pathology, including lacunar infarcts, and it is better than CT for defining exact anatomical localization.
Magnetic Resonance Imaging Neuroimaging in geriatric psychiatry
Suspected condition | Indicated neuroimaging study |
|---|---|
Sudden loss of consciousness
|
Noncontrast CT scan
|
Pituitary tumor (hyperprolactinemia)
|
MRI
|
Old vs. new lacunar infarct
|
Diffusion weighted imaging
|
Hippocampal atrophy
|
Coronal thin slice MRI
|
Wernicke’s encephalopathy
|
MRI to rule out midbrain hemorrhage
|
Note. CT = computed tomography; MRI = magnetic resonance imaging.
| |
A limitation of CT and MRI is that neither can differentiate between acute and chronic lesions. Diffusion-weighted imaging (DWI) overcomes this difficulty. DWI is based on the capacity of fast MRI to detect a signal related to the movement of water molecules between two closely spaced radiofrequency pulses (diffusion). This technique can detect abnormalities due to ischemia within 3–30 minutes of onset, whereas conventional MRI and CT images would still appear normal. Therefore, DWI is helpful in defining the clinically appropriate infarct when multiple subcortical infarcts of various ages are present.
The American Academy of Neurology recommends routine use of structural neuroimaging (noncontrast head CT or MRI) in the initial evaluation of all patients with dementia (Knopman et al. 2001). Recent studies also suggest novel uses for MRI in dementia. Schuff et al. (2009) showed that in the Alzheimer’s Disease Neuroimaging Initiative cohort, patients with MCI and AD show progressive hippocampal loss over 6 months and then accelerated loss over 1 year. NeuroQuant, an FDA-approved software program, automatically quantifies volumes of brain structures and may be useful for measuring progressive hippocampal loss in patients. MRI measurements of cortical thickness, ventricular volume, and mean diffusivity may also help to distinguish normal pressure hydrocephalus from other neurodegenerative disorders (Ivkovic et al. 2013; Moore et al. 2012).
Positron Emission Tomography Imaging
PET imaging has recently been incorporated into dementia workup, and imaging agents that specifically bind amyloid or tau are being studied to determine their clinical utility. The main risk of PET imaging is exposure from radioactive imaging agents, which currently are mostly 18fluorodeoxyglucose (FDG) based and have a half-life of about 110 minutes. PET has two important advantages: high sensitivity and quantification of distribution of the radioactive tracer; its main disadvantage is the lack of spatial resolution. MRI has several important advantages: high-resolution imaging of structures, excellent anatomical contrast for soft tissue structures, and other useful measurements such as perfusion, diffusivity, and spectroscopy. PET-MRI hybrid imaging combines the advantages of each imaging modality but is currently limited by lack of availability to many patients.
FDG-PET Imaging
FDG-PET imaging can be useful in distinguishing AD from frontotemporal dementia (FTD) when the clinical diagnosis is unclear. On FDG-PET imaging, AD causes hypometabolism predominantly in posterior temporoparietal association and posterior cingulate cortices, whereas FTD causes hypometabolism in the frontal lobes and anterior temporal and anterior cingulate cortices. In one study, visual interpretation of FDG-PET metabolic and statistical maps was superior to clinical assessment, with a diagnostic accuracy of 89.6% (Foster et al. 2007). Medicare has approved payment for FDG-PET imaging in patients who meet the criteria for both AD and FTD and need clarification of their diagnosis.
Amyloid PET Imaging
Florbetapir, flumetamol, and florbetaben (a chemical cousin of florbetapir) are FDA-approved fluorine-based radioactive PET imaging agents that bind to brain β-amyloid plaque and are indicated to detect the presence of β-amyloid neuritic plaques in people with progressive cognitive decline. There are no major differences among these agents. Because amyloid PET scans expose patients to radioactivity (equivalent to 100 or more X-ray examinations), it is not recommended that patients have multiple scans during their lifetime. The scans are interpreted visually as positive, negative, or indeterminate by an experienced reader. Readers vary in their interpretation and expertise; for this reason, there is a risk of a wrong interpretation. Furthermore, a negative scan only indicates the state at the time of the scan and does not preclude that a scan would be positive a year or so later. β-Amyloid plaques are currently required for a confirmatory diagnosis of Alzheimer’s dementia; a negative scan indicating a low probability of β-amyloid plaques may point to other causes for the person’s dementia. The negative predictive value of amyloid scans for future progression is high. The positive predictive value of amyloid scans is close to 50%; therefore, positive scans themselves do not necessarily mean that the patient has AD (Zannas et al. 2012). Positive scans can be seen in numerous conditions, such as dementia with Lewy bodies, late-stage Parkinson’s dementia, and prion disorders, and even in normal elderly individuals who carry an allele producing the ε4 type of apolipoprotein E. The effect of amyloid scans on changing patient management or diagnosis was tested in a multicenter uncontrolled study with some promising results but needs to be confirmed further in controlled studies (Grundman et al. 2013). About 30% of all cognitively normal elderly individuals and 40%–50% of subjects with MCI will have a positive scan, and studies suggest that people with a positive scan progress faster than do those with a negative scan (Doraiswamy et al. 2012). However, until further study, these scans are not indicated for use to screen cognitively normal individuals or to predict future decline in at-risk individuals. Currently, Medicare and insurance companies do not reimburse these scans, except in special circumstances, and further effectiveness studies are under way to determine appropriate coverage.
Tau PET Imaging
Tau PET imaging is also actively being developed with hopes of understanding the role of tau tangles in the pathophysiology of AD. Further studies are needed to determine the specificity of tau imaging agents and the forms of tau to which they bind, as well as to validate findings with postmortem studies (Chien et al. 2014).
Electroencephalography
Electroencephalography is a technique in which scalp electrodes allow the measurement of cortical electrical activity. A skilled reader can interpret the electroencephalographic (EEG) waveforms to identify the presence of epileptic activity, the slowing of electrical activity, or a patient’s sleep stage. EEG testing is most useful in a psychiatric evaluation of individuals with known or suspected seizure disorders. Although a history of brain injury or trauma with mental status changes or psychosis may be an important indication for an EEG evaluation, imaging studies are generally preferred for diagnostic clarification in these situations.
In elderly individuals, EEG changes occur in both delirium and dementia, but these changes are not specific to a given diagnosis. In delirium, except that caused by alcohol or sedative-hypnotic withdrawal, electroencephalograms typically display slowing of the posterior dominant rhythm and increased generalized slow-wave activity. Electroencephalography has limited clinical use in this area because the diagnosis of delirium is typically made clinically, increased slow-wave activity is seen in other disorders, and the electroencephalogram provides minimal information about the causes of delirium. However, EEG testing is useful for distinguishing between depression and “quiet” delirium because no EEG changes are seen in depression, whereas generalized slowing is seen in delirium.
Likewise, there are EEG changes in dementia. AD results in multiple changes in EEG parameters. Although Kowalski et al. (2001)) reported that the degree of EEG change (slowing of normal background activity) is correlated with cognitive impairment, there are also reports that worsening of EEG results does not always parallel the clinical deterioration. Various treatments, including cholinesterase inhibitors, may mitigate EEG changes in individuals with mild dementia (Kogan et al. 2001). However, significant negative correlations have been found between frontal theta activity and hippocampal volumes (Grunwald et al. 2001). Although electroencephalography currently has limited clinical utility, the COGNISION trial is under way to determine whether electrical signals produced during task performance (event-related potentials) may be helpful for the diagnosis of AD (National Institute on Aging 2010).
EEG testing may be useful, however, when CJD is a consideration in the differential diagnosis. CJD is a rare, rapidly progressive prion disease characterized by dementia and neurological signs that may include gait disturbances and myoclonus. Electroencephalography may play an important role in diagnosing this disease: periodic sharp-wave complexes are strongly associated with CJD, with a sensitivity of 67% and a specificity of 86% (Steinhoff et al. 1996). Although electroencephalography is an important diagnostic tool when considering CJD, it is important to remember that periodic sharp-wave complexes may also occur in AD and dementia with Lewy bodies.
Genetic Testing
Genetics in geriatric psychiatry is covered in more detail in Chapter 3, “Genomics in Geriatric Psychiatry.” In this section, intended to serve as an introduction to genetic testing, we briefly discuss a well-researched test examining for APOE alleles, pharmacogenomics, and ethical and psychological concerns related to genetic testing.
APOE Testing
Extensive research has attempted to identify genetic markers for AD. Mutations on chromosomes 1, 14, and 21 have been linked to rare forms of early-onset familial AD; such findings may help families make decisions about pregnancies. One of the most studied genes for AD is APOE. This gene encodes for an astrocyte-secreted plasma protein that is involved in cholesterol transport. APOE may also play a role in the regeneration of injured nerve tissue. There are three possible alleles (ε2, ε3, ε4) of the APOE gene that may be combined in a heterozygous (ε2/ε3, ε2/ε4, ε3/ε4) or homozygous (ε2/ε2, ε3/ε3, ε4/ε4) fashion.
Multiple epidemiological studies have documented that the presence of the ε4 allele is a risk factor for AD. Additionally, the presence of ε4 alleles increases the specificity of the diagnosis of AD. Despite these associations, the presence of an ε4 allele, even a homozygous ε4/ε4 genotype, is not diagnostic for AD. The APOE story may be even more complicated; Roses et al. (2010) found that another factor, TOMM40 poly-T polymorphism, may be linked to APOE and that together these may affect the mean age at onset of AD. A clinical trial is under way to further validate this finding. APOE testing is not currently recommended to predict dementia risk in asymptomatic individuals. Arguments against routine testing include the lack of an effective treatment to modify the disease course and the lack of evidence that APOE status may influence current supportive treatments.
Pharmacogenomics
Most pharmacogenetic tests are designed to detect certain alleles that may be correlated with psychotropic response or serious psychotropic-related adverse events. The first FDA-approved pharmacogenetics test, the AmpliChipR CYP450 Test made by Roche Diagnostics, includes the assessment of 27 alleles in cytochrome P450, family 2, subfamily D, polypeptide 6 gene CYP2D6 (Malhotra et al. 2012). This assessment of the CYP2D6 allele is purportedly helpful for clinicians who are trying to determine an appropriate starting dose for numerous psychotropic drugs (including several SSRIs, TCAs, and antipsychotics) that are metabolized by CYP2D6. Ultrarapid metabolizers (about 1% of the population) may require higher dosages to have therapeutic levels, whereas poor metabolizers (about 7%–10% of Caucasians and 1% of Asians) may require lower dosages to achieve similar levels. A number of studies have also examined various alleles to try to detect those individuals who are at higher risk for serious adverse events, such as metabolic syndrome, from taking antipsychotics (Malhotra et al. 2012). Currently, based on the available studies, the FDA recommends performing the HLA-B*1502 allele test for carbamazepine-induced Stevens-Johnson syndrome only for individuals of Asian descent.
Psychiatrists should ask themselves a few questions before ordering the results of a pharmacogenetics test for clinical purposes. First, is the patient from the specific population in which the test has been shown to be valid? For example, the HLA-B*1502 allele test was validated in Asian but not Caucasian populations. Second, what is the evidence for predictive power of the test in the clinical (vs. the laboratory) setting? Demonstration of biologically accurate results and quality control is an essential part of any laboratory test but does not necessarily equate to clinical validity. Third, what is the likelihood that the pharmacogenomic test will sufficiently explain the observed phenotype? Although an allele may be associated with a high risk of an adverse outcome, it may not explain the majority of cases seen.
Additionally, as discussed in the next section, ethical and psychological concerns must be considered. Does the patient fully appreciate the implications of undergoing such tests in the clinical setting? For example, a patient may agree to the release of test results to a health insurance company or another third party, believing at the time that the test is designed for a particular purpose (e.g., detection of risk of weight gain from antipsychotics). However, future studies may show that this allele is associated with development of an unrelated disease process such as cancer, and this discovery may have consequences that the patient did not anticipate if proper counseling was not received. Therefore, collaboration with a genetics counselor is essential before any genetic testing is performed in the clinical—and arguably in the research—setting.
Ethical and Psychological Concerns in Genetic Testing
The results of genetic testing may have significant psychological, social, and personal repercussions. These possible effects are likely to be of less concern for a patient already diagnosed with dementia than for his or her family members faced with the risk of inheriting the disease. The offspring of a patient with AD are at increased risk for the disease based on family history alone. If a parent with AD is found to be homozygous for the APOE ε4 allele, the children, who will have at least one copy of the allele, have at least two to three times the average risk of developing AD. Unfortunately, this knowledge does not allow offspring to anticipate with certainty whether and when they will develop AD. Also, no treatment is available to APOE ε4 allele carriers to prevent the disease.
A positive family history of late-onset AD has been associated with a distinctive phenotype in MCI—namely, lower levels of β-amyloid 42 and higher levels of t-tau in the CSF—suggesting that other genetic factors are present besides APOE (Lampert et al. 2013). Previously, family members were discouraged from being tested due to stigmatization or worry because of increased risk of AD. However, a number of AD prevention trials are now being geared toward asymptomatic individuals at higher risk for dementia (usually with a family history), so interested individuals may wish to discuss the issue with their physicians and genetic counselors.
Beyond personal and psychological concerns, there are also financial concerns. Genetic testing should be confidential. The inappropriate release of such information could result in job loss or lack of insurability. While the Genetic Information Nondiscrimination Act of 2008 prohibits health insurers from engaging in genetic discrimination, some health insurance organizations and providers of long-term-care insurance, life insurance, or disability insurance are exempt from this prohibition (National Human Genome Research Institute 2014). Medical and life insurance in particular might be exceedingly difficult to obtain if insurance agencies gain access to this information.
In the end, however, genetic testing is yet another tool at the disposal of patients and clinicians. It is a tool with much untapped potential. It also carries significant risks that are different from the risks associated with other laboratory tests described in this chapter. As with other procedures, clinicians must make sure that patients or patients’ families clearly understand not only the benefits but also the risks before they proceed with testing.
Omics Technologies
Since the inception of the Human Genome Project, high-throughput omics technologies have shown immense promise to revolutionize medicine in the decades to come. There is, however, an absence of widespread use and acceptance of these tests in the clinical setting for various reasons, including need for replication, need for demonstration of validity in the general population, and costs. Nevertheless, given the high likelihood that psychiatrists will have patients who will ask to have these tests performed or will bring in results of these tests from elsewhere, it is important that clinicians have a basic conceptual understanding of the general purpose and challenges that may arise in the interpretation of these omics technologies. Given the rapid development of this field, an exhaustive review is not possible. Nevertheless, many of the same questions regarding the clinical interpretation of pharmacogenetic tests (see earlier section “Pharmacogenomics”) can also be applied to the other omics technologies.
The purpose of the omics technologies is to examine the changes that can occur at different levels within an organism due to both physiological and pathophysiological processes. Table 5–5 briefly describes various omics technologies (Valdes et al. 2013). The overall concept is that these technologies sample the process of how the organism is functioning from the beginning product (the genome) to its end product (its metabolites), as well as in between (epigenomics, transcriptomics, and proteomics). These findings can be used to determine at which stage(s) critical differences or modifications associated with certain types of outcomes (particularly in diseases or adverse medication effects) may arise.
Omics Technologies Omics technologies
Omic technology | Example |
|---|---|
Genomics
|
Examination of somatic differences in the nucleus and mitochondria genomes
|
Epigenomics
|
Examination of epigenetic changes (including DNA methylation and histone modification) that affect whether parts of the DNA sequences can be transcribed
|
Transcriptomics (expression profiling)
|
Examination of RNA transcripts, namely the expression of genomic material, including microRNAs, which can negatively regulate or degrade transcripts
|
Proteomics
|
Examination of proteins, including posttranslational modifications such as phosphorylation, ubiquination, and glycosylation, that can affect the proteins’ functioning
|
Metabolomics
|
Examination of metabolic content of cell or organism (including changes in protein, nucleic acid, carbohydrates, and lipids)
|
Source. Valdes et al. 2013.
| |
Conclusion
Laboratory testing can provide invaluable information in both the diagnosis and the treatment of geriatric psychiatry patients. Clinicians should carefully interpret laboratory values in the context of patients’ histories and other available data. The role of neuroimaging, CSF biomarkers, and various “omics” in clinical care is the focus of future research and will revolutionize the care of the geriatric psychiatric patient. Future directions for laboratory values include detection of populations who may be at risk for certain psychiatric disorders (e.g., dementia) and prediction of which individuals may respond or not respond to certain treatments for psychiatric disorders.
Key Points
- Laboratory testing is an essential component of the psychiatric evaluation for elderly individuals, who often present with comorbid medical illnesses.
- Laboratory tests are also useful in monitoring medication side effects. New guidelines have been proposed to monitor patients taking atypical antipsychotics.
- Neuroimaging is useful in evaluation of a variety of neuropsychiatric illnesses including, but not limited to, dementia.
- Genetic testing has great potential in geriatric psychiatry but currently has limited clinical utility. Important ethical issues should be considered when using genetic testing.
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