Dementias: Etiologies and Differential Diagnoses
Patricio F. Reyes, MD
Jiong Shi, MD, PhD
Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
Early and accurate diagnosis is the major objective in dementia evaluation. To achieve this goal, a comprehensive examination must include a thorough medical history; careful medical and neurologic examinations; assessment of cognitive, behavioral, and activities of daily living; laboratory tests; and neuroimaging studies.
Key Words: activities of daily living, Alzheimer's disease, behavior, cognition, dementia, Lewy body, neurodegeneration, neurofibrillary tangles, neuritic plaques, Parkinson's disease
Abbreviations used: AD, Alzheimer's disease; ApoE, apolipoprotein-E; CNS, central nervous system; CT, computed tomography; MR, magnetic resonance; NPH, normal pressure hydrocephalus; PCR, polymerase chain reaction; PD, Parkinson's disease; PET, positron emission tomography; TBI, traumatic brain injury
The graying of the world has heightened interest in normal aging and dementia. This trend largely reflects that the elderly is the fastest growing segment of the population. Therefore, dementias, which usually affect the late middle-aged and elderly, have become a major health care problem. Typically, patients with dementia exhibit gradual yet progressive decline in cognitive functions, changes in personality and behavior, and deterioration in their activities of daily living.
Frequently, onset of symptoms is difficult to ascertain because normal older individuals may show similar manifestations. The symptom complex of dementia evolves over several months to years. Therefore, early recognition is crucial to offer comprehensive therapy that includes pharmacologic and nonpharmacologic strategies, psychosocial intervention, and advice for timely legal and financial planning. A major hurdle that needs to be overcome is the misperception by certain ethnic groups that dementia is a natural consequence of aging; hence, it requires no diagnostic or therapeutic intervention. It is imperative that educational programs designed to eradicate such a false notion incorporate culturally based and sensitive strategies.
Diagnosing and treating dementias have placed considerable financial strain on our healthcare system and individual families. Affected patients are forced to quit their jobs or to seek early retirement whereas spouses and other family caregivers may have to reduce their working hours to care for their loved ones. The same caregivers have to endure increased emotional and physical stress due to the protracted clinical course of many dementias. Furthermore, healthcare costs have been estimated to rise steeply when medical conditions are complicated by cognitive decline and behavioral symptoms. Management of these symptoms often requires sophisticated tests, special referrals, and expensive prescription drugs.
Etiology and Differential Diagnosis
A wide spectrum of systemic and neurological disorders can give rise to signs and symptoms of dementia (Table 1). The differential diagnosis includes degenerative (Alzheimer's, Parkinson's, or Pick's disease), emotional (depression), metabolic (organ failure), neoplastic (carcinomatous meningitis), traumatic (TBI), immunologic (multiple sclerosis), infectious (Creutzfeldt-Jakob disease), endocrine (hypothyroidism), nutritional (vitamin B12 deficiency), and cerebrovascular diseases.
Diagnosis can be challenging since most cases of dementia are in middle-aged and older individuals who are vulnerable to both systemic and neurologic diseases. Consequently, many are prescribed multiple medications that can produce or exacerbate neuropsychiatric symptoms or that cause drug interactions. Drug-related adverse events such as extrapyramidal symptoms associated with chronic neuroleptic exposure could easily be mistaken as evidence of Parkinson's disease with dementia or as AD with Lewy bodies.
Among the several etiologic entities, degenerative CNS disorders compose the overwhelming majority. When dealing with such diseases, there are fundamental tenets that should be noted. First, neurodegeneration takes several months or years to manifest clinically. Therefore, even when early signs and symptoms are confirmed by sensitive clinical measures, it must be assumed that the pathologic process began many months or years earlier. Its onset may be insidious yet its course is progressive. Neurodegeneration usually denotes bilateral brain involvement although neurologic signs may be asymmetrical. As the disease progresses, the process may become diffuse or multifocal caused by transsynaptic degeneration of afferent and efferent systems. Risk factors may be known but many entities are idiopathic.
Presenting symptoms may occur after certain emotional or physical trauma or exposure to certain medications, in particular those with strong anticholinergic properties, possibly exacerbating the cholinergic deficiency in AD. Several years ago we reported patients who developed progressive dementia after receiving eye drops. Death of a loved one may trigger depression, memory loss, and language difficulty whereas surgery and general anesthesia may herald persistent agitation, confusion, hallucinations, and memory difficulty. It would be prudent to perform neurobehavioral testing before surgery in vulnerable patients who need general anesthesia.
Among the neurodegenerative disorders, AD accounts for at least 65%, making it the most common cause of dementia among the middle-aged and older. Ten to 15% have vascular dementia secondary to various forms of cerebrovascular disease. Nevertheless, recent neuropathologic studies have indicated that in 30 to 35% of cases, lesions associated with AD and vascular dementia coexist. PD, the third leading cause of dementia and considered for several decades as a primary extrapyramidal disorder, may be accompanied by dementia in at least 30% of cases.