Evaluation of Dementia

Amy A. Pruitt

Dementia is defined as the acquired decline in cognitive ability that impairs activities of daily living. New terms defining cognitive impairment with lesser degrees of functional disability have been introduced. Memory is the most common ability lost with dementia, but speech, judgment, and mood may all be altered in varying proportions. The prevalence rises rapidly with age, starting at 1% at age 60 years and doubling every 5 years to nearly 40% by the age of 85 years. Over 600,000 persons with advanced dementia in the United States require institutional care. With the aging of the US population, the social consequences of the problem are likely to be staggering if no major changes in prevention and treatment are implemented. Dementia accounts for more admissions and hospital inpatient days than does any other geriatric psychiatric condition. Median survival and rate of decline depend on age at diagnosis and can range from 3 to 20 years.

Many illnesses can cause dementia. Alzheimer disease (AD), the most common cause of dementia, is the sixth leading cause of death in the United States affecting an estimated 5.4 million Americans 65 years of age or older. By 2050, it is estimated that 14 million people will carry the diagnosis and health care expenditures for people with dementia will exceed $1 trillion. About 15% of patients with dementia have significantly reversible causes or complicating conditions amenable to treatment such as depression, drug-induced cognitive decline, hydrocephalus, or an operable brain tumor.

It is estimated that one third of patients meeting criteria for dementia remain undiagnosed, but prompt recognition of dementia is essential, not only for the initiation of a diagnostic workup but also to protect the patient from avoidable harm, such as that due to a fall, drug overdose, fire, inadequate nutrition, and in-hospital delirium in the setting of concurrent medical illness.

Each patient requires a careful workup to properly identify the underlying cause. Primary physicians should know how to distinguish dementia from other, more specific cortical deficits (aphasia, agnosia, isolated memory deficit) and should be able to perform a screening examination for potentially reversible disease. Special subsets of patients, such as those with more rapid onset of dementia (months to less than 2 years), require specific attention and urgent diagnostic evaluation plus neurologic referral.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6 and 7)

Dementia results from disruption of normal cerebral circuits in characteristic regions or patterns that define the syndrome. Cholinergic circuits are important for memory and are impaired in AD, while in patients with non-AD dementias, serotonergic, glutaminergic, noradrenergic, or dopaminergic pathways may be selectively impaired. The condition is typically chronic and slowly progressive, but a subset of cases with an infectious or autoimmune pathophysiology are more likely to present subacutely.

Mild Cognitive Impairment

Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia. It is classified into two subtypes: amnestic, with significant memory impairment that does not interfere with daily life, and nonamnestic in which skills other than memory are impaired. MCI is present in 10% to 20% of persons older than 65. People with MCI are at risk for the development of dementia with an annual rate of 5% to 10% conversion to dementia. Current studies seek predictors of progression to dementia and biomarkers to assess utility of therapeutic interventions that might alter the course of disease.

It is important but not always possible to distinguish the early stages of dementia from nonprogressive cognitive changes (benign forgetfulness) that occur in normal aging. The term “mild cognitive impairment” usually refers to an isolated loss of memory without problems in other cognitive domains and with intact activities of daily living.

Dementia

The onset of dementia is usually insidious, although a few conditions evolve rapidly. Rapidly progressive dementia heralds a different set of differential diagnostic possibilities. Patients initially may be noted to be slightly forgetful, with attention and concentration deficits and increasing repetitiousness or inconsistencies in their usual behavior. Later in the course of the process, patients may display increasingly impaired judgment, an inability to abstract or generalize, and personality changes, reacting with rigidity, perseveration, irritability, and confusion to minor changes in the environment. Affective disturbances or aggressive behavior may be prominent, and in extreme forms, patients lose all vestiges of their original personality, are unable to participate in matters of personal hygiene and nutrition, and are left helpless.

Dementia is often progressive (as in degenerative diseases), but it may be static (as in a posttraumatic brain injury state). Depending on the pathologic condition that causes dementia, indications of disease outside the areas of the brain responsible for cognitive and behavioral change may or may not be found. Concomitant disorders of extrapyramidal function are particularly common.

Some conditions that result in dementia may also cause mental retardation (e.g., Down syndrome). Patients with dementia may or may not be psychotic, and a patient with psychosis may or may not have any evidence of cognitive decline consistent with dementia.

Pathophysiology and Clinical Presentation of Primary Neurologic Conditions

Alzheimer Disease

As the leading cause of dementia, AD accounts for well more than half of cases among the elderly and affects 15 million people worldwide. Its incidence increases with advancing age producing a prevalence of 25% in persons over the age of 90 years. Most cases are sporadic, but familial autosomal dominant forms of the disease exist. Mutations in the gene for the amyloid precursor protein and the genes for presenilins 1 and 2 cause the uncommon, dominantly inherited forms of the disease that become symptomatic before the age of 60 years, and the e4 variant of apolipoprotein E is associated with the sporadic form and some later-onset familial forms. A mutation in the TREM2
gene (which codes for microglial phagocytic capacity) has also been linked to AD. Both apo-E4 and TRANS2 gene mutations increase risk by three- to fourfold. Such mutations suggest a “loss-of-function” pathophysiology for AD. Elevated serum levels of homocysteine and aspects of the metabolic syndrome have been found to be independent risk factors for AD, increasing the relative risk nearly twofold and suggesting future avenues for midlife intervention.

No specific physical signs are characteristic, although frontal lobe release signs and secondary mild extrapyramidal features may be present. A high probability of the diagnosis can be determined according to the criteria established by the Alzheimer’s Disease and Related Disorders Work Group, which have been updated. Progressive worsening of memory with impairment of at least one other cognitive function is the hallmark of the disease. About two thirds of patients with moderate to severe dementia who have no other illness that can cause dementia (e.g., cerebrovascular disease, hypothyroidism) are given the diagnosis of probable AD.

Pathologic changes in the brain appear up to two decades before the patient manifests symptoms. Neuropathologic study reveals neuronal loss, neurofibrillary tangles composed of τ-protein, and senile plaques containing the β-amyloid peptide. Basal forebrain degeneration reduces the acetylcholine content. The loss of this transmitter correlates with memory impairment. Frequently, vascular dementia and AD coexist, and both pathologies are found postmortem.

The International Working Group for New Research Criteria for Alzheimer’s Disease has introduced distinctions targeted at identifying presymptomatic AD, defined by biomarkers (amyloid beta tau in CSF, amyloid beta tracer uptake in neuroimaging and positron emission tomography [PET] scanning). Pending evidence of their impact on clinical outcomes, the National Institute on Aging and the Alzheimer’s Association have recommended the restricted use of preclinical diagnostic testing to research environments.

Dementia with Lewy Bodies

This increasingly appreciated but probably widespread and underdiagnosed idiopathic condition has features of Alzheimer and Parkinson diseases, which leads to considerable diagnostic confusion and the potential for therapeutic mismanagement. Recognition is important because these patients manifest marked sensitivity to neuroleptic drugs, which may exacerbate symptoms (see Chapter 173).

The pathologic hallmarks are the widespread presence of Lewy bodies (intracytoplasmic inclusions) in the cortex, amygdala, hippocampus, and pars compacta of the substantia nigra and nucleus ceruleus, with a loss of neuronal density in the latter areas. Unlike patients with AD, these patients have only mild brain atrophy grossly and normal density of the neocortex.

The initial presentation is often one of visual hallucinations, episodic delirium, fluctuating cognitive difficulties, and parkinsonism and extrapyramidal motor symptoms (dysarthria, poor coordination of voluntary movements). As in AD, short-term memory impairment and a progressive decline in cognition interfere with social and occupational functioning. In early stages, the memory impairment may be mild, and periods of nearly normal functioning occur intermittently. Deficits in attention and visual-spatial and frontal-subcortical skills are nonetheless evident.

Core features include recurrent visual hallucinations that are well formed and detailed, fluctuating consciousness, and spontaneous motor features of parkinsonism and extrapyramidal disease. Other characteristics include falls, syncope, transient loss of consciousness, hallucinations in other domains, systematized delusions, and, as noted, sensitivity to neuroleptic medications. The rate of clinical decline is generally more rapid than that of AD.

Multi-infarct Dementia

“Hardening of the arteries” with cerebral hypoperfusion has been a common, although mistaken, lay view of the cause of dementia. Vascular disease or multiinfarct dementia, however, is the second most common cause of dementia in the United States, accounting for 10% to 20% of dementia cases. Although the exact contribution of vascular dementia to the rate of progression of AD is a subject of ongoing study, it appears that AD patients with hypertension, diabetes, atrial fibrillation, smoking history, or known carotid disease are at risk for a vascular contribution to their dementia.

The characteristic clinical course is one of stepwise progression if discrete large-vessel occlusions occur and is more gradual if the infarctions are primarily lacunar (see Chapter 171). The infarctions may be large and heralded by clearly defined episodes of neurologic injury or develop subclinically as small lacunar strokes contributing to a slow decline in intellectual function. Magnetic resonance imaging (MRI) may reveal multiple lacunar infarctions and a loss of periventricular white matter. Most patients have evidence of upper motor neuron injury (lateralized weakness, brisk reflexes, or Babinski signs). Multiinfarct dementia is sometimes referred to as a subcortical dementia, characterized by apathy, slowness, and decreased memory retrieval. The development of dementia within 1 year of a first stroke is a subject of significant research.

Independent risk factors for dementia such as elevations in low density lipoprotein (LDL) cholesterol and homocysteine may exert their effect through vascular mechanisms because both are established risk factors for atherosclerotic vascular disease (see Chapter 26). Aggressive reduction in LDL cholesterol reduces the risk of stroke (see Chapter 171); whether it will reduce the risk of dementia remains to be established. Reduction in homocysteine is yet to be proven to reduce cardiovascular risk (see Chapter 31).

Mixed Disease

As patients age, the brain becomes increasingly vulnerable to insult. Moreover, the risks for vascular and degenerative diseases increase. For this reason, it is likely that a large percentage of cases of dementia in the very elderly are of a mixed type, with both vascular disease and AD as underlying conditions. The significance of this notion of mixed disease is that it focuses attention on various potential causes of dementia and the importance of controlling risk factors (e.g., improving diabetic or hypertensive control).

Normal-Pressure Hydrocephalus

Normal-pressure hydrocephalus (NPH) is a communicating hydrocephalus resulting from impaired cerebrospinal fluid (CSF) resorption into venous sinuses. Most often, the precipitant is unknown, but the condition can occur when resorption is blocked as a consequence of prior meningeal inflammation, trauma, or subarachnoid hemorrhage. Dementia, gait disturbance, and urinary incontinence comprise the classic triad, but these symptoms are nonspecific and common in many conditions affecting older patients. The diagnosis is suspected clinically and radiographically when CT or MRI demonstrates large ventricles without prominent vascular disease or widening of cortical sulci.

Space-Occupying Lesions

Space-occupying lesions such as chronic subdural hematoma or slowly growing tumors of the brain produce variable dementia, depending on their size and location. When they are located on the orbital surface of the frontal lobe or the medial surface of the temporal lobe, patients may present primarily with cognitive defects and no other focal signs of cerebral tumor. The development of a progressive unilateral headache (see Chapter 165), a new neurologic deficit, or a change in personality may provide
a clue to the presence of a mass lesion. More diffuse infiltrating neoplasms such as primary central nervous system lymphoma may present with a nonspecific picture of cognitive decline.

Depression

Depression can produce the rapid onset of a true cognitive deficit that is reversible with appropriate treatment. Other symptoms of depression (hopelessness, low self-esteem, earlymorning awakening, fatigue, anhedonia; see Chapter 227) almost always predate the onset of the dementia and help to suggest the diagnosis. Unlike patients with AD, depressed patients will complain of memory loss during a mental status examination. Although depression alone can produce significant reversible cognitive impairment, severe mood disturbance may also accompany other causes of dementia, such as AD or Parkinson disease.

Other Primary Neurologic Conditions

Other primary neurologic conditions associated with dementia and specific neurologic deficits include frontotemporal dementia, Parkinson disease (see Chapter 174), Wilson disease, severe multiple sclerosis (see Chapter 172), Creutzfeldt-Jakob disease (CJD), neurosyphilis, and Huntington disease (Table 169-1).

Frontotemporal dementia is associated with predominantly frontal and temporal lobe pathologic involvement. The age of onset is usually earlier, and cognitive deficits differ from those of AD, with early personality change and impairment of executive function (the ability to modify behavior in response to changing stimuli, solve problems, organize, think abstractly, and avoid perseveration).

Parkinson disease (see Chapter 174) and Huntington disease are sometimes referred to as subcortical dementias because they present with significant motor dysfunction and no prominent aphasia or agnosia.

CJD, the notorious prion-related condition associated with mad cow disease, is among the most common causes of rapidly progressing dementia.

TABLE 169-1 Neurologic Diseases Associated with Intellectual Dysfunction

Disease	Physical Signs	Clinical Features
Alzheimer disease	Frontal lobe release signs, extrapyramidal signs	Enlarged ventricles and cortical atrophy by CT or MRI
Normal-pressure hydrocephalus	Gait disorder,^a incontinence	Enlarged ventricles with little or no cortical atrophy
Dementia with Lewy bodies (Lewy body disease)	Visual hallucinations, periodic confusion, parkinsonism	Marked exacerbation of extrapyramidal symptoms with use of standard neuroleptics
Multi-infarct dementia	Focal deficits	Stepwise course; multiple areas of infarction, often subcortical, by CT or MRI
Parkinson disease	Extrapyramidal signs^a	Usually present only after disease has been evident for several years
Intracranial tumor	Focal signs, papilledema	Often subacute evolution, seizures possible
Neurosyphilis	Frontal lobe signs, optic atrophy, Argyll Robertson pupils	Positive serology serum and CSF
HIV infection	Variable systemic involvement	Positive HIV, cortical atrophy; dementia may be presenting symptom
Creutzfeldt-Jakob disease	Myoclonus,^a cerebellar signs, eye movement abnormalities	Subacute course; EEG has specific abnormalities; MRI shows diffusion-weighted hyperintensities
Huntington disease	Choreiform movements,^a corticospinal signs	Often positive family history; caudate atrophy by CT or MRI
Multiple sclerosis	Brainstem signs, optic atrophy, corticospinal signs	Usually long-standing disease; episodic illness with remissions; often extensive white matter abnormalities by MRI
Wilson disease	Extrapyramidal signs^a, hepatic dysfunction, Kayser-Fleischer rings^a	Onset in adolescence or young adult life, psychiatric disorders
Progressive supranuclear palsy	Failure of vertical downgaze,^a extrapyramidal signs^a	Eye movement abnormalities; differentiate from Parkinson disease; unresponsive or only transiently responsive to levodopa
^aInvariably present; all other physical signs are neither invariably present nor pathognomonic.
CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.

Other Causes of Dementia

Toxins, infections, metabolic disorders, and nutritional disorders may affect the brain and result in dementia (Table 169-2). Frequently, more than one pathologic cause is present.

Medications/Intoxication

The patient with a progressive degenerative dementia may be taking an excess of a medication that is exacerbating the primary process, or the drug itself may be causing an apparent loss of cognitive abilities. Medications capable of producing dementia in patients without other underlying conditions include opiates and the numerous neurotropic agents available. Less obvious but frequently prescribed medications causing or aggravating dementia include the anticholinergic preparations used in bladder and movement disorders, antihypertensives, and sedatives. These agents are high on the list of causes of disease that can be arrested or reversed.

Infection

Any infection involving the brain can produce a picture of diffuse cognitive impairment. Neurosyphilis, HIV infection (see Chapter 13), and cryptococcal infection spread into the central nervous system to produce dementia, often with great regularity. Infectious agents responsible for subacute conditions like CJD (prion-induced infection related to mad cow disease) and progressive multifocal leukoencephalopathy (due to reactivation of dormant JC virus) are resistant to treatment.

Endocrinologic, Nutritional, and Metabolic Disorders

This category of etiologies represents some of the more reversible causes of dementia, which tend to present with clinical manifestations of the underlying condition, as well as with altered cognitive function, although sometimes these manifestations may be subtle. Particular attention to nutritional history is warranted in patients who have undergone bariatric surgery
for weight loss and whose adherence to vitamin replacement regimens may be erratic.

TABLE 169-2 Systemic Conditions Associated with Intellectual Impairment

Infectious
	Syphilis with central nervous system involvement
	HIV infection with central nervous system involvement
	Cryptococcal infection of the central nervous system
	Progressive multifocal leukoencephalopathy
Endocrine
	Hypothyroidism and hyperthyroidism
	Panhypopituitarism
	High-dose glucocorticoid therapy
Metabolic
	Vitamin B₁₂ deficiency
	Thiamine deficiency
	Niacin deficiency (pellagra)
Chemical Poisons
	Alcohol
	Metals (lead, mercury)
	Aniline dyes
Drug Intoxications
	Barbiturates
	Opiates
	Anticholinergics
	Lithium
	Bromides
	Haloperidol
	Antihypertensives

Endocrine.

Thyroid dysfunction due to hyperthyroidism or hypothyroidism may lead to impaired but reversible cognitive function. In the elderly, the clinical manifestations may be absent or atypical (see Chapters 103 and 104). The administration of highdose corticosteroid therapy can acutely alter cognitive function.

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