Dementia

Overview

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) designates cognitive disorders on a spectrum of cognitive and functional decline: delirium, mild and major neurocognitive disorders, and their etiological subtypes. The term dementia is retained for consistency; it was used in the fourth edition (DSM-IV) to describe a syndrome with a decline in memory, as well as an impairment of at least one other domain of higher cognitive function (e.g., aphasia [a difficulty with any aspect of language]; apraxia [the impaired ability to perform motor tasks despite intact motor function]; agnosia [an impairment in object recognition despite intact sensory function]; or executive dysfunction [such as difficulty in planning, organizing, sequencing, or abstracting]).

While dementia is encompassed by the term major neurocognitive disorder (MNCD), for a diagnosis of MNCD to be made there must be evidence of significant cognitive decline in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual motor, or social cognition) based on concern of the individual, a knowledgeable informant, or the clinician, as well as by objective measures of substantial cognitive impairment on standardized neuropsychological testing or quantified clinical assessment. Several important qualifiers are included in the definition: i.e., the condition must represent a change from baseline, social or occupational function must be significantly impaired, and the impairment does not occur exclusively during an episode of delirium, or cannot be accounted for by another Axis I disorder, such as major depression.

Many elderly adults complain of difficulties with their memory (e.g., with learning new information or names, or finding words). In most circumstances, such lapses are normal. The term mild cognitive impairment (MCI) was coined to recognize an intermediate category between the normal cognitive losses associated with aging and with dementia. While MCI was subsumed under cognitive disorder not otherwise specified in DSM-IV, this less severe level of cognitive impairment most closely corresponds with “mild neurocognitive disorder” in DSM-5. Diagnostic criteria include evidence for a modest decline in cognition from a previous level of performance in one or more cognitive domains based on concern of the individual, a knowledgeable informant, or clinician, and based on objective evidence of cognitive decline. Important qualifiers include lack of interference with independence in everyday activities, and not exclusively occurring during an episode of delirium, and not accounted for by another Axis I disorder. MCI is characterized by a notable decline in memory or other cognitive functions as compared with age-matched controls. MCI is common among the elderly, although estimates vary widely depending on the diagnostic criteria used and the assessment methods employed; some, but not all, individuals with MCI progress to dementia. According to some studies, individuals with MCI may progress to Alzheimer's disease (AD) at a rate of 10%–15% per year. Risk factors for conversion from MCI to AD include carrier status of the E4 allele of the apolipoprotein E ( APOE ) gene, clinical severity, brain atrophy, specific patterns of CSF biomarkers and cerebral glucose metabolism, and AB deposition. Further identification of factors that place people at risk for progression of cognitive decline is an active area of research.

Epidemiology of Dementia

The most common type of dementia (accounting for 60% to 80%) is AD. Among the neurodegenerative dementias, Lewy body dementia is the next most common, followed by frontotemporal dementia (FTD). Vascular dementia (formerly known as multi-infarct dementia) can have a number of different etiologies; it can exist separately from AD, but the two frequently co-occur. Indeed, there is increasing awareness that AD is often mixed with other dementia causes. Dementias associated with Parkinson's disease (PD) and Creutzfeldt–Jakob disease (CJD) are much less common. Given the challenges of making an accurate diagnosis of dementia subtypes in epidemiological studies, and in light of neuropathological data suggesting that mixed pathologies are more common than discrete subtypes, the proportion of dementias attributed to different subtypes must be interpreted with caution.

The Role of Age of Onset

The onset of dementia is most common in the seventies and eighties, and is quite rare before age 40. Both the incidence (the number of new cases per year in the population) and the prevalence (the fraction of the population that has the disorder) rise steeply with age. This general pattern has been observed both for dementia overall, and for AD in particular, with the prevalence increasing exponentially with age, increasing from 3% among people age 65–74 years to nearly 50% in those >85 years. Estimates of the prevalence of dementia vary to some extent depending on which diagnostic criteria are used. The incidence of dementia of almost all types increases with age such that it may affect 15% of all individuals over the age of 65 years, and up to 45% of those over age 80. However, the peak age of onset varies somewhat among the dementias, with FTD and vascular dementia tending to begin earlier (e.g., in the sixties) and AD somewhat later.

Dementia is the main cause of disability among older adults and not surprisingly the economic burden of dementia is enormous. Moreover, it is expected to rise steeply with anticipated demographic shifts. A substantial fraction of the increased burden will fall on developing countries, as a larger fraction of the population survives to old age. Indeed by one estimate, while there were 36.5 million people world-wide with dementia in 2010, the number of people living with dementia is expected to double every 20 years, with most of those living in low and middle income countries. Because AD and many other neurodegenerative disorders have an insidious onset, the precise age of onset is indeterminate. However, the approximate age of onset (i.e., within 2 to 5 years) is critical from both the personal and the public health points of view. It may offer an important leverage on disease risk and morbidity. A sufficient delay in onset can be equivalent to prevention with a late-onset disorder. Later onset can also decrease the burden of disease by pushing it later into the life span. From the research perspective, age of onset shows a robust relationship to genetic risk factors, and may have value as an outcome in genetic and other causal models.

Evaluation of the Patient with Suspected Dementia

The diagnostic criteria for dementia require that a number of confounding disorders have been ruled out, particularly delirium and depression. Of note, an underlying diagnosis of dementia may predispose a patient to delirium; thus, further evaluation of cognitive deficits is required once delirium has been treated successfully. Delirium may be differentiated from dementia in several important ways; the onset of delirium is typically acute or subacute, the course often has marked fluctuations, and level of consciousness and attention are impaired.

Depression also may be difficult to distinguish from dementia, particularly as the two diagnoses are often co-morbid. Further, depression alone may cause some cognitive impairment; in such cases it may precede AD by several years. Certain features (such as a more acute onset, poor motivation, prominent negativity, and a strong family history of a mood disorder) favor a diagnosis of depression.

Establishing a precise etiology of dementia ( Box 14-1 ) whenever possible allows for more focused treatment and for an accurate assessment of prognosis. Although reversible causes will be found in less than 15% of new cases, a diagnosis may help a patient and his or her family to understand what the future holds for them and to make appropriate personal, medical, and financial plans.

History should never be obtained from the patient alone; family members or others who have observed the patient are essential informants for an accurate history. The patient often fails to report deficits, usually because the patient is unaware of them (anosognosia). Ideally, family members should be interviewed separately from the patient so that they can be as candid as possible.

When obtaining a history one should determine the nature of the initial presentation, the course of the illness, and the associated signs and symptoms (including those that are psychiatric or behavioral). These areas are important in determining disease etiology (e.g., recognizing the characteristic abrupt onset of vascular dementia as opposed to the gradual onset of AD).

Review of systems should be extensive and must include inquiry about gait and sleep disturbance, falls, sensory deficits, head trauma, and incontinence. Obtaining the full medical history may reveal risk factors for stroke or for other general medical or neurological causes of cognitive difficulties. The psychiatric history may suggest co-morbid illnesses (such as depression or alcohol abuse), particularly if prior episodes of psychiatric illness are elicited.

Up to one-third of cases of cognitive impairment may be at least partially caused by medication effects; common offenders include anticholinergics, antihypertensive agents, various psychotropics, sedative-hypnotics, and narcotics. Any drug is suspect if its first prescription and the onset of symptoms are temporally related.

Family history can be helpful in determining the type of dementia, as discussed later. A social and occupational history is useful when assessing pre-morbid intelligence and education, changes in the patient's level of function, and any environmental risk factors.

A general physical examination is essential with particular focus paid to the cardiovascular system. Physical findings can also suggest endocrine, inflammatory, and infectious causes. A complete neurological examination (including assessment of cranial nerves, sensory and motor functions, deep tendon reflexes, and cerebellar function) may reveal focal findings that suggest vascular dementia or another degenerative disorder, such as PD. Screening for acuity of vision and hearing is important because it may reveal losses that can masquerade as, or exacerbate, cognitive decline.

Psychiatric examination may reveal evidence of delirium, depression, or psychosis. On formal mental status testing, such as with the Folstein Mini-Mental State Examination, and other cognitive tests ( Table 14-1 ), documentation of particular findings, in addition to the overall score, allows cognitive functions to be followed over time.

Laboratory evaluation should include a complete blood count (CBC) and levels of vitamin B ₁₂ and folate, a sedimentation rate, electrolytes, glucose, homocysteine, blood urea nitrogen (BUN), and creatinine, as well as tests of thyroid function and liver function. Screening for cholesterol and triglyceride levels is also useful. Syphilis serology should also be included on an initial panel. A computed tomography (CT) scan of the brain, without contrast, can also be useful in identifying a subdural hematoma, hydrocephalus, stroke, or tumor.

Additional studies are indicated if the initial work-up is uninformative, if a particular diagnosis is suspected, or if the presentation is atypical ( Table 14-2 ). Such investigations are particularly important in young patients with rapid progression of dementia or an unusual presentation. Neuropsychological testing may be quite useful, and is essential in cases where a patient's deficits are mild or difficult to characterize. Briefer screening tools, such as the MMSE, have poor sensitivity and specificity for dementia, particularly in highly educated or intelligent patients. Such tests also generally fail to assess executive function and praxis.

Other diagnostic tests can supplement initial assessment when indicated. Magnetic resonance imaging (MRI) of the brain is more sensitive for recent stroke and should be considered when focal findings are detected on the neurological examination; in addition, MRI scans can identify lesions not apparent on physical examination, so it should always be considered when the diagnosis is unclear. An electroencephalogram (EEG) may be used to identify toxic-metabolic encephalopathy, complex partial seizures, or CJD. A lumbar puncture (LP) may be indicated when cancer, infection of the central nervous system (CNS), hydrocephalus, or vasculitis is suspected. Testing for the human immunodeficiency virus (HIV) is indicated in a patient with appropriate risk factors, because up to 20% of patients with HIV infection develop dementia, although dementia is uncommon as an initial sign. Heavy metal screening, as well as tests for Lyme disease, Wilson's disease, and autoimmune diseases, should be reserved for patients in whom these etiologies are suspected.

Alzheimer's Disease

Pathophysiology

In his initial 1907 case, Alois Alzheimer identified abnormal nerve cells and fiber clusters at autopsy in the cerebral cortex using what was then a new silver-staining method. These findings, considered to be the hallmark neuropathological lesions of AD, are known as neurofibrillary tangles (NFTs) and neuritic plaques (NPs) ( Figure 14-1 ). Beta-amyloid protein, present in soluble form in the brain, but also a major component of plaques, is thought to play a central pathophysiological role in the disease, perhaps via direct neurotoxicity. NFTs are found in neurons and are primarily composed of anomalous cytoskeletal proteins (such as hyperphosphorylated tau), which may also be toxic to neurons and contribute to AD pathophysiology.

However, the mechanisms by which changes in tau and beta-amyloid mediate neuronal death and dysfunction remain important unanswered questions and active areas of research. Two proposed methods of tau-mediated toxicity include NFT toxicity and conformational abnormalities of tangles, including a spreading process through multiple brain regions, in which abnormal tau can catalyze formation of abnormal tau in other cells through a prion-like process. Soluble and diffusible beta-amyloid may cause cytotoxicity and synaptotoxicity, with amyloid plaques serving as reservoirs for sequestration of soluble oligmers.