The effective clinician will locate all relevant case data while evaluating the reliability and bias of the sources. He or she will be aware of valid diagnostic categories and classifications, locate and evaluate relevant scientific literature and apply those data to individual cases. The clinician will also select treatment, evaluate efficacy and side effects, decide on alternative therapy, and determine satisfaction and concerns of the patient, family and referring physician.
Formulating the differential diagnosis
Working diagnoses are ordered in likelihood as a list of differential diagnosis, in line with the approach of the great 19th-century neurologist Jean-Martin Charcot, who linked clinical signs with specific lesions.13The clinician first asks, “Is the problem neurologic?” A comprehensive history and examination may fail to disclose a neurologic diagnosis. The second question is,
“Where is the problem localized? Is it in the peripheral or central nervous system? Is it at the level of the brain, brainstem, spinal cord, peripheral nerve, neuromuscular junction, or muscle?”The skill of neuroanatomical localization is honed over years and relies on knowledge of anatomy and physiology. Focal or asymmetric findings such as right-sided weakness or numbness, loss of vision in one eye, or left-sided neglect are more often associated with tumors or strokes than with degenerative conditions. The third question concerns time course and pattern of fluctuations of disease. Alzheimer’s disease and related disorders follow a chronic course of worsening over years.
Acute changes over hours to days suggest different conditions including stroke, seizure, or medication side effects. Repeated episodes of acute impairment followed by recovery can reflect medication effects, seizures or migraines.
Cognitive and behavioral impairments in the elderly include many conditions, often with subtle differences in presentation and findings. Criteria for diagnostic testing may depend on the costs and benefits of making or missing a diagnosis. Discussion of the more common or more important conditions is provided below in the section“Discussion of the Diagnosis with the Patient.”As a brief reference, Table 6.5 includes some of these conditions and their distinguishing features. The ICD-10 is the 10th revision of theInternational Statistical Classification of Diseases and Related Health Problems(ICD),30a medical classification led by the World Health Organization (WHO).
It contains codes for more than 14,000 diseases, signs, symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, including most of interest to the aging mind and brain. TheDiagnostic and Statistical Manual of Mental Disorders(DSM-5®)31 is the American Psychiatric Association taxonomy that guides research, policy, and reimbursement for many of these conditions.
Additional testing and investigations
Clinicians who address neurological and behavioral function in elderly patients gather data and results that trigger testable working diagnoses, which are often listed under the taxonomies pro- vided by ICD-10 and DSM-5. Additional testing can help refine diagnostic possibilities. These 117 Medical Assessment of the Aging Mind and Brain
(A)
Figure 6.3 Standard mental status screening tools. (A) KSTME and (B) MoCA.
118 T. Scott Diesing and Matthew Rizzo
(B)
Figure 6.3 (Continued)
119 Medical Assessment of the Aging Mind and Brain
Table 6.5 Examples of disorders that affect cognition and thought.
Condition Pathophysiology Presentation Common Findings Workup Treatment
Alzheimer Disease
• Degenerative
• Accumulation of neurofibrillary tangles and plaques in the brain
• Chronic progressive amnesia followed by other cognitive changes
• Predominant impairment of short term recall.
• Some difficulty with language, executive, or visuospatial function
• Normal imaging or atrophy of the hippocampi
• Cholinesterase inhibitors or NMDA antagonist may slow the degeneration Frontotemporal
Dementia
• Heterogeneous degenerative processes
• Abnormal protein inclusions within neurons
• Chronic progressive changes in personality, executive function, and language.
• Disinhibition, apathy, aphasia.
• 5–30% will have concamminant motor neuron disease
• Early on, may score well on neuropsych testing.
• Imaging shows frontal or temporal lobe atrophy
• Symptomatic and behavioral
Vascular Dementia
• Accumulation of ischemic injuries or strokes.
• Stepwise decline in multiple cognitive domains
• Variable cognitive impairment
• Motor and sensory deficits
• Imaging shows multiple strokes
• Other vascular risk factors
• Stroke prevention and vascular risk factor mitigation Lewy Body
Dementia
• Degenerative
• Accumulation of abnormal alpha- synuclein protein.
• Chronic progressive fluctuating cognition, visual hallucinations, and Parkinsonism
• Triad of dementia, visual hallucinations, &
Parkinsonian features.
• Sensative to neuroleptics
• Imaging findings are nonspecific.
• REM behavior disorder on sleep study
• Autonomic dysfunction common
• Symptomatic and behavioral
• rivastigmine sometimes helpful with cognitive and behavioral symptoms.
Parkinson Disease
• Degenerative loss of dopaminergic neurons in the basal ganglia
• Chronic progressive tremor, slowness, and gait difficulties
• Bradykinesia
• Resting tremor
• Rigidity
• Shuffling stooped gait
• Imaging findings are nonspecific.
• Abnormal basal ganglia signal on PET
• Levadopa or dopamine agonists
Huntington’s Disease
• Degenerative genetic, autosomal dominant
• Trinucleotide (CAG) repeats in the huntington gene
• Chronic progressive psychiatric, cognitive dysfunction with abnormal movements.
• Chorea, or akinetic rigid state in advanced disease.
• Dementia
• Depression, psychosis, hallucinations
• Atrophy of the caudate nucleus on imaging
• Genetic testing for trinucleotide (CAG) expansion
• Symptomatic and behavioral
• tetrabenazine may be helpful
Normal Pressure Hydrocephalus
• Excessive cerebrospinal fluid (CSF), likely due to impaired absorption
• Subacute or chronic difficulty with walking, cognition, and incontinance
• Triad of gait apraxia, subcortical dementia, urinary incontinance
• Ventriculomegaly on imaging
• Improvement after removal of CSF by spinal tap
• Repeated spinal taps or ventricular shunting
Subdural hematoma
• Accumulation of blood between the meningeal dura and the arachnoid membranes
• May be abrupt onset or gradual.
• Altered mental status
• Unilateral weakness or numbness
• Extra-axial blood on non-contrast CT brain
• Neurosurgical drainage
Delirium • Heterogeneous impairment of mental functions
• Fluctuating confusion often with agitation or somnolence
• Fluctuating level of consciousness with disorientation, misperceptions, &
inattention.
• All studies may be negative.
• Correction of the underlying cause.
Psychosis • Psychiatric disorder • Loss of contact with reality.
• Bizzar behavior and thinking.
• Delusions
• Hallucinations
• Disorganized thoughts
• All studies may be negative.
• Anti-psychotic medications
investigations may include biomarkers in the blood or cerebrospinal fluid (CSF) reflecting neuronal death, inflammation, or vascular damage. Imaging of brain structure and morphology are common. Imaging and electrophysiologic tools probe altered metabolism or activation within the brain. Cognitive and behavioral assessments are included under the rubric of neuropsycholog- ical testing. Referral to specialists such as sleep medicine and psychiatry are often helpful. A flow chart of the general medical approach to cognitive changes is provided. (Figure 6.4). Chapter 25
Graphic 1: Medical evaluation of cognitive changes
Directed Medical Evaluation ad/or
CSF Testing History:
-Life changes or new stressors -Sleep problems -Medication changes
-Fever or illness
Physical
examination Labs:
-TSH, B12, UA, CBC, BMP
Imaging:
-MRI or CT
EEG Imaging:
-MRI or CT
EEG
Labs:
-TSH, B12, UA, CBC, BMP
Normal or borderline Dementia
or MCI Psychiatric
illness
Monitor Sleep study Further workup
Focal Non-focal
–
–
– –
– + –
+
+ +
+ +
Neuropsychometric testing
Figure 6.4 Medical evaluation of cognitive changes.
122 T. Scott Diesing and Matthew Rizzo
and chapter 21 detail the diagnostic evaluation of encephalopathy and cognitive disorders in the elderly respectively.
Laboratory and blood testing Laboratory and blood tests to evaluate patients with altered mental status depend on the specific clinical situation. Common blood tests to assess metabolic factors related to neuronal function include glucose levels, thyroid function, vitamin levels including B12 and D, electrolytes, kidney and liver function. The elderly patient is vulnerable to dehydration due to ambient heat, diuretics, and reduced fluid intake, resulting in electrolyte disturbance, cognitive inefficiency, and weakness. Urinary tract infections may cause abrupt change behavior or mentation in the elderly. Resulting bacteremia can cause encephalopathy and a medical emer- gency. Urinalysis, urine culture, and blood cultures are essential to evaluate these patients. Chronic infections such as HIV, hepatitis or syphilis can produce dementia or focal brain dysfunction. More specific testing depends on the situation such as blood gasses (oxygen and carbon dioxide) for chronic respiratory disease, serum ammonia levels for liver failure, and medication levels.
Neuropsychological testing Neuropsychological tests are a critical tool for cognitive assessment, as detailed in Chapter 7. Results may clearly show cognitive impairment as can be seen in moderate or advanced dementia. They may suggest“borderline,”or MCI, or point to a psychiatric diagnosis.
They provide a clear baseline for future comparison for judging decline after some time, say, a year has elapsed. Formal neuropsychometrics can help to discriminate between Alzheimer’s disease, vascular dementia, focal dementias limited to specific lobes of the brain, or cognitive impairment due to injury of the connecting axons deep in the brain. Neuropsychometric testing can also screen for mood disorders, anxiety and malingering. Formal neuropsychometrics is the most sensitive way to determine the presence or degree of cognitive impairment in patients with a high baseline functional level.
Formal neuropsychometric testing is usually performed by a specialized neuropsychologist using standardized tests that consider age, gender, and education. The testing approach is determined by the neuropsychologist and based on the patient’s baseline intellect and the clinical situation. For patients with average or above average cognitive baseline and mild early disease, this may be the best way to identify and characterize the deficits. Tools such as the Barona index attempt to estimate premorbid intellect.14Some patients with high levels of education or functional baseline may produce a false negative result on mental status screening, a ceiling effect. Some patients may be too high functioning for the screening test to detect any problem. For example, a retired professor with an early dementia may take years before she or he has difficulty with calculations or spelling words backwards. Neuropsychometric testing is appropriate for these situations.
Imaging Structural brain imaging often uses computerized tomography (CT) or magnetic resonance imaging (MRI). CT is expeditious, well-tolerated by most patients and useful for detecting acute bleeding and large structural abnormalities. It has lower resolution than structural MRI, is susceptible to bony artifact, and involves a modest radiation exposure. MRI provides more structural detail than CT for identifying atrophy, small strokes, and inflammation. It is more expensive and requires the patient to lie still in a small space for up to an hour, risking claustropho- bia or discomfort related to the aging body. CT and conventional MRI test brain structure, not function, and can be performed with or without a contrast media to identify inflammation or breakdown of the blood-brain barrier. CT contrast has the risk of nephrotoxicity and allergic reactions, while MRI contrast has a lower risk of side effects. Both modalities can also perform noninvasive angiography to assess for vascular disease leading to strokes or hemorrhages.
Functional studies of the brain can be considered in two broad groups. The first group consists of imaging studies that involve measurement of cerebral hemodynamics and includes positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and transcranial Doppler sonography (TCD). Functional MRI imaging pairs the standard MRI images of the brain 123 Medical Assessment of the Aging Mind and Brain
with techniques measuring cerebral blood flow. The combination of fMRI and blood oxygenation level dependent (BOLD) techniques exploit dynamic changes in the regional balance of oxyhemo- globin to deoxyhemoglobin in the capillary bed adjacent to active neurons, revealing which areas of the brain are active during certain cognitive tasks. Similarly, fluorodeoxyglucose positron emission tomography (FDG-PET) and single photon emission CT (SPECT) studies show regional brain activity with different temporal and spatial resolution compared to fMRI. A detailed discussion of the various MRI techniques and their uses is provided in chapter 8.
Electroencephalography (EEG), event-related potentials (ERPs), and magnetoencephalogra- phy (MEG) noninvasively assess electromagnetic activity of the brain. MEG assesses magnetic fields produced by the electrical currents of the brain itself, and may be a possible biomarker for Alzheimer’s disease.15PET and fMRI are currently the most common noninvasive imaging techniques for evaluation and localization of neural activity. Their temporal resolution is poor compared to electrophysiological techniques such as ERPs. Emerging optical imaging techniques such as fast near infrared spectroscopy (NIRS) may provide both spatial and temporal resolution.
Further reading on PET studies can be found in chapter 9.
Electroencephalography EEG assesses brain electrical activity with high temporal resolution.
Compared to MRI and CT, it provides little information about brain structure but greater detail of function. It is a physiologic test that provides information in real time about the degree and location of brain activity. Its main use in clinical practice is to evaluate for seizures and epilepsy.
A technician affixes small electric leads on the scalp and face. The leads are then connected by wires to the recording device. The test is not painful nor is it usually uncomfortable. The patient must be able to hold reasonably still. The electrical potentials produced by the neurons are displayed on a computer screen as continuous waveforms. The recording is affected by the patient’s wakefulness and attentiveness among other things. The patterns of electrical activity may appear suppressed, irregular or exaggerated with injury or impairment.
EEG may be helpful in the evaluation of cognitive impairment due to its ability to identify focal or asymmetric cortical dysfunction. Additionally, certain patterns or findings have been associated with specific conditions. For example, in frontotemporal dementia, the EEG waveforms are often slow or suppressed in the corresponding frontal and temporal lobes. Periodic bisynchronous sharp-wave discharges are associated with Creutzfeldt-Jakob Disease.16EEG may show a treatable or reversible condition such as the excessive frontal beta pattern of benzodiazepine use, or generalized triphasic waves as seen in hepatic encephalopathy. Patients who are having frequent nonconvulsive or complex partial seizures may present as progressive cognitive impairment, and EEG may detect the interictal pattern or fragments of subclinical seizures. EEG and evoked potential in aging are reviewed in chapter 10.
CSF and biomarkers CSF testing may be obtained as part of an extensive evaluation of cognitive changes especially in atypical situations. Lumbar puncture and CSF testing can help exclude a nondegenerative cause such as chronic infections, normal pressure hydrocephalus, or certain cancers. In the case of normal pressure hydrocephalus, removal of a volume of CSF can be therapeutic. In most degenerative dementias, the CSF is normal or shows a mild elevation of total CSF protein. Biomarkers in the CSF continue to be studied as a way to determine the nature and prognosis of a person with cognitive impairment. The list of potential CSF biomarkers is evolving and includes tau and amyloid-beta. The amount and proportions of these markers in the CSF has been correlated with some neurodegenerative conditions. In Alzheimer’s disease, for example, the CSF may show increased levels of tau protein and relatively low levels of amyloid-beta-42 compared to amyloid-beta-40.17It is crucial to keep in mind that these studies are highly special- ized and in some cases experimental and may not be supported by the patient’s health care plan.
124 T. Scott Diesing and Matthew Rizzo
Genetic testing There is a growing amount of knowledge about the relationship between genetics and dementia. However, genetic testing is infrequently used in the clinical evaluation of cognitive changes due to the lack of preclinical therapeutic interventions. Much of the knowledge involves the genetics of Alzheimer’s disease. Theε4 allele of theAPOEgene on chromosome 19 has been linked to an increased risk of developing Alzheimer’s dsease.19,20At present, this test has more research than clinical value since its results imply risk rather than diagnosis of the disease. The genes APP,PSEN1, andPSEN2have been linked to a form of early onset Alzheimer’s disease. Although rare—comprising less than 1% of all Alzheimer’s disease cases21,22—testing for these genes may have some relevance in cases of hereditary early onset dementia. However, inherent in genetic testing are the ramifications for family members which should be discussed with the patient prior to any genetic test—and the family should ideally be involved in the discussion.
Consultations Specialist consultations are sometimes needed in the evaluation of brain dysfunc- tion. In addition to neuropsychology, these consultations may include psychiatry, sleep medicine, geriatrics or a cognitive and dementia subspecialty neurologist. A psychiatric specialist may assess whether emotional or psychological disorders are interfering with the mental abilities (see chapter 24.).
A visit to the patient’s home can provide a picture of their functional abilities. As this is not often practical, simulation is being investigated as a tool to evaluate patients in complex situations, including driving.18