Dementia is the term to describe intellectual and cognitive deterioration of sufficient severity to interfere with normal functioning. Dementia is not a specific disease and can variably affect multiple aspects of cognitive function including memory, orientation, visuospatial perception, language, and higher executive functions, for example, planning, organizing, and sequencing. This differs from delirium, which implies an often acute and reversible, global disturbance of mental function (discussed further in Chapter 3).

EPIDEMIOLOGY

Dementia is most common in the elderly but can occur at a younger age, particularly in those with a hereditary predisposition. Approximately 5% of people between the ages of 65 and 70 years have dementia; this increases to more than 45% above age 85 years. Alzheimer disease (AD) accounts for 50% to 70% of cases of dementia. Cerebrovascular disease may account for an additional 15% to 20%, and the other causes presented in Box 12-1 account for most of the rest. The societal financial burden of dementia is substantial, with recent studies estimating more than $150 billion spent in the United States annually on dementia-related care, a cost on par with those of cancer and heart disease.

CLINICAL MANIFESTATIONS

There is some degree of cognitive slowing that accompanies normal aging. In general, however, most patients with actual dementia have more significant and progressive difficulties, often affecting short-term memory, followed by an indolent deterioration of cognitive function that may involve language, praxis, and personality. Many dementing illnesses manifest characteristic symptoms and clinical findings that are helpful in establishing an etiologic diagnosis.

DIAGNOSTIC EVALUATION

The initial recognition of dementia is difficult. Normal aging can mimic some of its features. Rarely is the patient aware of cognitive deterioration; in most cases, the family brings the patient to the doctor months or years after problems have started. Recent research has demonstrated, however, that subjective cognitive decline reported by older adults can be an early indicator of dementia, even in the absence of objective cognitive dysfunction. Thus, the most important information in the diagnosis of dementia is the clinical history (including reports by relatives) and the physical examination, especially a very detailed mental status examination. Diagnosis of the cause of dementia consists of matching the major clinical features of the individual patient with the characteristics of known dementing illnesses. Of note, it is important to rule out an underlying depression as the cause for cognitive symptoms, as the associated cognitive abnormalities of depression can mimic dementia (“pseudodementia”). In addition, depending on the clinical history and examination, laboratory studies may be helpful in finding reversible causes of dementia. Box 12-2 summarizes some tests to consider in the workup of cognitive dysfunction.

BOX 12-1. Causes of Dementia

CAUSES OF DEMENTIA

ALZHEIMER DISEASE

In 1907, Alois Alzheimer, a German clinician and neuropathologist, published the landmark case of a 51-year-old woman with deterioration of her mental state. Her autopsy showed the classic pathology of Alzheimer disease (AD): neurofibrillary tangles (NFTs) and senile plaques in the cerebral neocortex and hippocampus.

BOX 12-2. Tests to Consider in a Patient with Dementia

CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; EEG, electroencephalography; HIV, human immunodeficiency virus; MRI; magnetic resonance imaging.

Clinical Manifestations

“Doctor, my mother is 75 years old, and over the last 3 years I have noted that she is having more difficulty with her memory. She remembers her marriage 50 years ago, but she does not remember that we were here yesterday. She asks the same questions repeatedly and forgets my answers. She is unable to balance her checkbook, and yesterday she could not find the way home from the drugstore.” This history illustrates the characteristic features of AD. At the beginning of the illness, the examination shows no difficulty with language, reasoning, or performance of normal social and personal behaviors. Only those close to the patient notice small slip-ups, suggesting that something is wrong (becoming lost while driving, misplacing objects, the kitchen stove left unattended, missed appointments, loss of social and interpersonal interactions). Later, the patient has more difficulty with activities of daily life.

As the disease progresses, other aspects of cognitive function are lost, including the ability to speak, understand, and make decisions. Characteristically, in contrast to patients with vascular dementia, elementary neurologic functions (motor, visual, somatosensory, and gait) remain normal until very late in the disease. Psychiatric manifestations are common at this time: personality changes (apathetic or impulsive), aggressive behavior (physical or verbal), paranoid thoughts and delusions (persecution, things being stolen), sleep disturbances (the word “sundowning” is used to describe worsening psychiatric manifestations during the evening and night), hallucinations (uncommon, and often a side effect of medications), and depression.

With the exception of those patients with identified mutations in known causative genes (APP, PSEN1, and PSEN2), the diagnosis of AD is a clinical one and can only be confirmed with brain biopsy. The diagnosis is suggested by the clinical features and by the insidiously progressive course. Investigations are designed to exclude other causes of dementia (Box 12-2). Elevated tau protein and low amyloid-beta (Aβ)-42 levels in the cerebrospinal fluid (CSF) have been suggested as early diagnostic markers for AD. Magnetic resonance imaging (MRI)-based volumetric measurements may show reduction of up to 40% in the size of the hippocampus, amygdala, and thalamus. Functional neuroimaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) used to quantify cerebral metabolism and blood flow, may help to differentiate AD from other dementias. In AD, PET and SPECT scans show bilateral temporoparietal hypometabolism, but this is not specific enough to be diagnostic.

Pathology

The major pathologic features of AD are brain atrophy, senile plaques, and NFTs, associated with a substantial gliosis and loss of neurons in the cerebral cortex. NFTs represent intracellular accumulation of phosphorylated tau protein. Senile plaques are extracellular deposits of amyloid surrounded by dystrophic axons. How exactly each of the known gene mutations associated with AD causes these changes is not established. In the case of APP, mutations are known to cause increased Aβ production and change the normal structure of the protein, altering its recognition by metabolizing enzymes, therefore leading to a progressive accumulation of the peptide. Other pathophysiologic mechanisms have been proposed, including inflammatory, oxidative, metabolic, nutritional, and immune processes.

Treatment

At present, there is no satisfactory treatment for patients with AD. Therapy consists of the following:

•Preventing associated symptoms: This includes treatment of depression, agitation, sleep disorders, hallucinations, and delusions.

•Preventing or delaying progression: This includes therapy with acetylcholinesterase inhibitors such as donepezil or rivastigmine, as well as memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist.

•Prophylaxis: Until now, there have been no successful single-drug clinical trials demonstrating decreased dementia incidence. This may be due, in part, to the heterogeneity of the underlying cause of AD, prolonged time course of the illness, and the likely presence of a protracted, preclinical disease state. In addition to clinical trials focusing on lifestyle-related interventions (i.e., physical activity, diet), trials investigating preventative and disease-modifying drugs may one day provide therapeutic options for the aging population. Table 12-1 provides information regarding therapy for AD.

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