Dementia: Mild Cognitive Impairment, Alzheimer Disease, Lewy Body Dementia, Frontotemporal Lobar Dementia, Vascular Dementia

Dementia Management

The treatment of dementia requires pharmacologic and nonpharmacologic approaches. We will review general treatment strategies here. The target of treatment typically falls into one or more of three interdependent factors, namely (1) cognition, (2) behavior, and (3) functional capacity. Treatment of one factor may negatively impact the other factors. The literature on dementia treatments is too expansive for full review here. More detailed discussion of specific dementia treatment strategies follows in subsequent sections.

It is imperative to recognize and treat dementia as early as possible, with a goal to maximize and preserve quality of life for both patient and caregiver. Treatment of cognitive impairment involves intervention either to reverse, slow, or delay progression of cognitive decline. For the most part, currently available pharmacologic agents prove valuable only in delaying decline, perhaps preventing more severe disability and behavior problems. Behavior problems range from disturbances of mood to psychotic symptoms, apathy to agitation, anxiety, and stereotypic, purposeless, rituals. Treatment of behavioral disturbance must address the behavior that proves disabling for the patient or the caregiver. In many cases, nonpharmacologic approaches may suffice. This may include diverting the patient's attention, changing the subject of conversation, comforting the patient affectionately, or occupying the patient with a task. Environmental manipulation, caregiver support, and day programs all provide structure and routine for the patient with behavior problems and for his or her caregiver. In cases where such interventions prove less effective for behavior management, or safety is compromised by aberrant behavior, pharmacologic treatments should be used. The chosen medication should address the primary aspect of behavior aberration, such as antidepressants for low mood and vegetative symptoms, mood stabilizers for emotional lability, or antipsychotics for psychotic symptoms and combativeness. Prevention of functional decline requires comprehensive management of both cognitive and behavioral disturbances, as well as provision of support and education to the caregiver. Routine follow-up of patients with their primary caregiver is essential to maximize quality of life for all involved.

Dementia and Driving

One of the most difficult aspects of counseling dementia patients and families relates to safety of operating a motor vehicle. Driving safety in AD is well studied, and there is clear evidence that relative risk of crashes for drivers with AD, from mild to severe stages of dementia, is greater than accepted societal standards. Drivers with MCI seem to have risk for crashes similar to teenage drivers. Several studies link driving risk with dementia severity using the CDR scale. The CDR is an informant-based scale that includes direct assessment of the patient and information given by a knowledgeable informant. The CDR scores increase from 0 (normal) to 0.5 (possible dementia) to 1.0–3.0 (mild, moderate, severe dementia). Most clinicians do not routinely use this scale in their everyday practice, and therefore translating the scale scores into everyday terms may be difficult. For practical purposes, the CDR score of 0.5 loosely translates into MCI, whereas a CDR score of 1.0 or greater translates to dementia. There may be exceptions to these findings, and further research is required to find more specific patterns of cognitive impairment that lead to driving risk. Risk of driving in non-Alzheimer dementia is relatively unstudied. However, it is safe to assume that driving risk is increased also in this population.

Epidemiology

AD is the most common cause of dementia in adults, accounting for approximately 5 million cases of dementia in the United States. Age-specific disease incidence increases exponentially with advancing age; the risk of development of AD doubles every 5 years, beginning at 65 years of age. AD affects approximately 50% of the population aged 85 years and older. Given the growing elderly population in developed countries, projections of future AD prevalence show a fourfold increase through 2050. Because dementia is a major factor in healthcare costs, morbidity, and mortality, the high prevalence of AD places enormous burdens on the healthcare system. In many cases, diagnosis is delayed until an advanced stage, at which point caregiver stress is already high and treatment options are limited. Of the 5 million prevalent cases, only 3 million are diagnosed and only one-third of diagnosed cases receive treatment. Of those who receive treatment, the percentage receiving adequate doses and follow-up is unknown. It is very important for clinicians to understand the natural history of AD, recognize early warning signs, implement appropriate screening and diagnostic tools, prescribe appropriate treatment, and follow patients regularly.

Pathogenesis

There is pronounced gross cerebral atrophy clearly evident on both imaging studies and postmortem. Typically, the dementia of AD preferentially affects the frontal, temporal, and parietal cortex. This is particularly evident in the temporoparietal and frontal association areas and the olfactory cortex. In contrast, other primary sensory cortical areas are unaffected. In addition, the limbic system, subcortical nuclei, and the nucleus basalis of Meynert are preferentially affected. Microscopically, there is clear loss of both neurons and neuropil. The classic findings include senile plaques and neurofibrillary tangles ( Figs. 27.1 and 27.2 ). The white matter sometimes demonstrates a secondary demyelination.

β-Amyloid

AD is a neurodegenerative disorder thought to result from deposition of the protein β-amyloid in the brain. β-Amyloid is formed by processing of the amyloid precursor protein (APP), a protein that may help to regulate synaptic integrity and function, possibly by regulating excitotoxic activity of glutamate. APP is encoded on chromosome 21. It is processed at the cell membrane by secretase enzymes, called α-, β-, and γ-secretases. Two known membrane-bound proteins, called presenilins, comprise the active domains of the membrane-bound γ-secretase protein: presenilin 1 and presenilin 2 are encoded on chromosomes 14 and 1, respectively. Numerous genetic mutations of the presenilin and APP genes are known to cause familial, early-onset cases of AD. The familial forms of AD account for fewer than 5% of all AD cases. The known mutations account for approximately 50% of familial AD. In all cases the genetic mutation leads to an overproduction of β-amyloid that may be the first step in the subsequent cascade of neurodegeneration.

β-Amyloid is a short fragment of the APP, typically 40–42 amino acids in length, which accumulates outside the cell during APP processing ( Figs. 27.3 and 27.4 ). The tertiary structure of the 42–amino acid fragment is a β-pleated sheet that renders it insoluble. Consequently, it accumulates slowly, over many years, in the extracellular space and within synapses. In vitro studies confirm that β-amyloid is toxic to surrounding synapses and neurons, causing synaptic membrane destruction and eventual cell death. Transgenic mouse models show a clear association between accumulation of β-amyloid fragments, formation of amyloid plaques, and development of cognitive impairment.

In vivo, β-amyloid fragments coalesce to form “diffuse” or immature plaques, best seen with silver-staining techniques. However, diffuse plaques are not sufficient to produce dementia; many nondemented elderly patients have substantial depositions of diffuse plaques throughout the cortex, a condition termed pathologic aging. It is when these plaques mature into “senile” or neuritic plaques that dementia becomes more likely ( Fig. 27.5, top ). Senile plaques consist of other substances in addition to β-amyloid, including synaptic proteins, inflammatory proteins, neuritic threads, activated glial cells, and other components. Unlike diffuse plaques, senile plaques are composed of a central core of β-amyloid surrounded by a myriad of proteins and cellular debris. Senile plaques are distributed diffusely in the cortex, typically starting in the hippocampus and the basal forebrain. Senile plaque formation correlates with increasing loss of synapses, which correlates with the earliest clinical sign, namely, short-term memory loss. The anatomic pattern of progression gradually spreads to neocortical and subcortical gray matter of the temporal, parietal, frontal, and, eventually, occipital cortex. Subcortical nuclei become involved relatively late in the process.

Risk Factors

Epidemiologic studies identify several potential risk factors for AD. The most consistent risk factors include advanced age, family history (especially in first-degree relatives), and apolipoprotein E (ApoE) genotype. Other risk factors include hypertension, stroke, and fasting homocysteine levels ( Fig. 27.6 ). Because vascular risk factors are modifiable, they may affect risk reduction and treatment for patients with AD and those at risk for development of AD.

• 1

  Advanced age is the single consistently identified risk factor for AD across numerous all-international studies. AD incidence and prevalence increase with advancing age, leading to the hypothesis that AD would develop in all individuals if they lived long enough. The true incidence in persons older than age 85 years is difficult to ascertain because of sharp decline in life expectancy. However, there are many instances of nondemented elders where no pathologic evidence of AD is found at autopsy, including in centenarians. Therefore dementia is not considered a “normal” part of aging.

• 2

  Family history of dementia is another consistent risk factor in many studies; however, the most common form of AD occurs sporadically. Establishing accurate family history of dementia is difficult because many of these patients’ relatives may not have survived into older ages where dementia risk is greatest. Rare, early-onset, presenile (before age 65 years) forms of AD occur with an autosomal-dominant pattern of inheritance. The genetic basis for many hereditary AD forms is identified. Most mutations affect the genes that encode APP and the presenilins. Each mutation leads to increased deposition of amyloid in affected individuals, predisposing to earlier onset. Individuals with trisomy 21 (Down syndrome) also have a high deposition of β-amyloid. AD develops in all patients with Down syndrome by age 35 years.

• 3

  ApoE genotype is another genetic risk factor ( Fig. 27.7 ). The three common allelic forms of this gene, epsilon 2 through 4, are encoded on chromosome 19. The presence of an e4 allele is associated with increased risk of AD and younger age at onset. This risk is greatly increased in e4 homozygotes. Conversely, the e2 allele appears to impart a protective, risk-lowering effect, as replicated in numerous international, population-based studies. The association between the ApoE e4 allele and AD seems to be disease specific. There is no clear association between e4 and other neurodegenerative or amyloid-based diseases.

  

  The mechanism underlying this increased risk associated with the Apo e4 allele is not well understood but may relate to the role of ApoE in cell membrane repair. Phenotypically, the e4 cases have greater amyloid deposition than do the non-e4 cases. Although ApoE genotyping is available, it is not a diagnostic test for AD, nor is it recommended for routine testing. Most patients with AD are non-e4 carriers. ApoE genotyping is largely used in research, primarily as a biologic marker to differentiate cases. Some studies suggest differential response to medications in cases stratified by ApoE genotypes.

• 4

  In recent years, cerebrovascular disease and vascular disease risk factors have emerged as significant risk factors for AD. The presence of stroke increases the likelihood of dementia in old age. Diabetes, hypertension, and hyperlipidemia consistently elevate relative risk of dementia across international epidemiologic surveys of AD and dementia. Moreover, multiple observational studies show reduced risk among individuals receiving treatment for these conditions. This connection between AD and cerebrovascular disease may provide an important focus for premorbid dementia prevention. It is unknown whether secondary stroke prevention reduces the likelihood of dementia or its rate of progression. Nevertheless, assessment of stroke risk factors may become increasingly important for the management of dementia patients.

Clinical Presentation

The early signs of AD may be subtle ( Fig. 27.8 ). In the initial stages of AD, memory losses can be clinically distinguished from normal aging, although formal memory testing is often required to confirm suspicion of early dementia. The early signs of AD begin insidiously, progress slowly, and are often covered up by patients. Detection may be challenging even for close family members. The physician may observe changes in the patient's pattern of behavior, such as missing appointments or poor compliance with medications. It is important to discuss such issues openly with family members given the patient often cannot recall examples of memory problems. Indeed, it is common for patients to have limited insight into their deficit and for family members to initiate an evaluation for memory loss. In these early stages, patients maintain their social graces. It is not uncommon during mental status testing to discover the significant cognitive problems concealed by a patient's friendly and sociable affect. “Very pleasant” patients sometimes fool even seasoned geriatricians. The Alzheimer's Association lists 10 key warning signs of AD.

Commonly, AD begins with short-term memory loss, although atypical presentations sometimes develop. Often, patients have increasing forgetfulness of words and names, relying more on lists, calendars, and family members for reminders. Disorganization of appointments, bills, and medications becomes commonplace. Family members often notice increasing repetitiveness, patients asking the same question or repeating the same conversation minutes after it was completed. Patients may forget to convey telephone messages or turn off the stove, or lose track of where they place things. Moreover, their ability to recall these incidents is impaired. They “forget that they forget.” Affected individuals may become suspicious of others (e.g., thinking that misplaced items were stolen).

Language function gradually declines. Word-finding and name-finding difficulties are common even in very early stages. Naming impairment and gradual loss of comprehension, expression, or both are universal. The perception of the temporal sequence of events is affected and disorientation eventually becomes pervasive. Geographic orientation declines, first affecting patients’ ability to navigate in unfamiliar environments and later within their homes. Visuospatial skills decline and construction deficits may occur early.

Behavior and personality in patients with AD are often affected; combativeness, irritability, frustration, and anxiety become extremely common. Many patients seek medical attention only when family members are alarmed by behavioral changes, rather than because of their earlier progressive memory loss. Psychotic features may become prominent. Some patients also develop delusional thoughts and hallucinations, most commonly visual or auditory in nature. These may be benign, understated, hidden, or frightening and may lead to severe agitation. Family members may not speak freely in the patient's presence about these symptoms.

As cognitive and behavioral changes appear, the patients’ ability to maintain personal independence declines. Altered activities that may occur early include medication mismanagement, financial disorganization, burnt pots on the stove, and driving errors. Eventually patients require assistance with activities of daily living: personal hygiene/bathing, eating, dressing, and toileting. Often, by this stage, patients exhibit signs of parkinsonism characterized by midline rigidity, symmetric bradykinesia and hypokinesia, stooped posture, and shuffling stride. The risk of falling increases. Seizures occur in up to 20% of cases. Myoclonic jerks are increasingly noted in advanced stages.

Later stages of AD are characterized by loss of bladder and then bowel control, failure to recognize family members, and eventually severe akinesia, requiring total nursing care. The most common cause of death is aspiration pneumonia. On average, AD has a duration of approximately 8 years. However, this varies substantially. Some patients live 20 years or more. Nursing care marks an important endpoint for many patients and their caregivers. The most common causes for nursing home placement include behavioral problems, immobility, and incontinence.

The Alzheimer's Association provides a staging system to allow doctors and caregivers a frame of reference when discussing the patient's level of impairment and possible future progression. It is important to emphasize that not every patient will follow through these stages in the same way or at the same rate.

Differential Diagnosis

The absence of motor deficits early in AD differentiates it from most other dementias. Other dementias lacking motor signs include amnestic syndrome (Korsakoff encephalopathy), Pick disease, vascular dementia, and human immunodeficiency virus (HIV) dementia complex. Depression can also produce dementia-like symptoms without motor deficits. Poor concentration and short-term memory impairment result from lack of effort, disinterest, or distractibility. “Pseudodementia” due to depression is usually not progressive, and functional loss is often disproportionately severe relative to cognitive impairment ( Fig. 27.9 ).

Reversible causes of dementia without motor signs include toxic and metabolic causes of chronic delirium. Chronic use of medication with anticholinergic side effects (e.g., antihistamines and tricyclic antidepressants) is a possible cause of chronic delirium that may mimic AD. β-Blockers, digoxin, H ₂ blockers, and various antibiotics may also contribute to chronic delirium. Chronic mass effect, caused by a slow-growing tumor (see Fig. 27.9 ), may also produce reversible cognitive impairment.

Dementia with motor deficits includes a longer list of possibilities. Thyroid disease, vitamin B ₁₂ deficiency, and tertiary neurosyphilis are often considered; however, these conditions rarely cause dementia and usually present with characteristic metabolic or sensorimotor symptoms.

Normal pressure hydrocephalus is a relatively uncommon condition that late in its course may be characterized by a significant dementia (see Fig. 32.2 ). Typically, these individuals present with a broad-based magnetic gait as if their feet were partially glued to the ground. Eventually these patients may become unwittingly incontinent, unaware of their loss of sphincter control as the dementing process evolves. Although these patients most often have no identifiable cause, on occasion, they have previously sustained a subarachnoid hemorrhage or meningitis leading to poor CSF reabsorption. This leads to the characteristic hydrocephalus without an associated loss of cortical mantel. A CSF shunt may lead to a remarkable improvement.

The presence of spastic hemiparesis or dysarthria raises suspicion of cerebrovascular disease. Parkinsonism is associated with Parkinson disease (PD) and dementia with Lewy bodies (DLBs). Progressive ataxia occurs with multisystem atrophy. Chorea characterizes Huntington disease. As AD progresses to late stages, parkinsonism often becomes evident, making clinical differentiation from other parkinsonian diseases more difficult. AD may also coexist with cerebrovascular or Lewy body (LB) pathology to produce dementia with motor signs.

Dementia may be further characterized by cortical and subcortical cognitive features, which also helps to differentiate between different dementing diseases. Subcortical features include slower mental processing, slow retrieval of information, and often significant extrapyramidal motor signs, including bradykinesia or adventitious movements.

Diagnosis

The subjective complaint of memory impairment is not useful for dementia screening because it is a common complaint in older adults. Prospective evaluation of individuals aged 65 years who have complaints of memory loss show that dementia develops in fewer than 9% within a 5-year follow-up. However, dementia develops during a 5-year prospective follow-up in 50% of patients aged 85 years who had no complaints of memory loss at baseline. Consequently, clinicians must be proactive, particularly with patients aged 85 years or older, and screen for cognitive impairment.

Proper clinical assessment requires a detailed history, preferably provided by a trustworthy, knowledgeable informant particularly a spouse or child. The history should describe the cognitive decline, in temporal sequence, from earliest suggestion of cognitive impairment to most recent events. Examination in early stages may reveal no neurologic deficits other than cognitive impairment. In later stages, or in patients with coexisting neuropathology, such as stroke, there may be motor deficits or other focal central nervous system (CNS) findings on physical examination.

Mental Status Exam

The mental status examination (see Chapter 2 ) should assess all major cognitive domains, including M emory, A ttention, L anguage, C onstruction, O rientation, P raxis, and E xecutive function (MALCOPE). Standardized global measures of cognitive function such as the MMSE are of limited diagnostic value. The widely used MMSE is relatively insensitive to the milder stages of AD. Other tests, such as the Montreal Cognitive Assessment Test, include test items more suited to detecting earlier stages of cognitive impairment, allowing improved sensitivity for detecting MCI. Another measure, the Alzheimer Disease 8 (AD8) is an informant-based tool that may shorten screening considerably. It must be emphasized that such instruments are not diagnostic tests, and interpretation of results must take into consideration level of education, native language, and physical or sensory impairment that might affect performance.

Impaired recording of information characterizes the memory loss of early AD. The inability to record information occurs when patients cannot recall information even with practice and when given hints or cues. Additional early cognitive deficits in AD include dysnomia, reduced verbal fluency (especially in word categories), orientation to time, and construction impairment. Having the patient list as many category words as possible within 1 minute provides a test of verbal fluency. For example, patients try to list animals or words beginning with the letter s.

Clock drawing is useful when testing construction and executive function ( Fig. 27.10 ). Patients draw a clock, for example, indicating 1 : 45 on a blank sheet of paper. Their performance is observed from beginning to end, including the shape and size, number order and placement, hand size and placement, etc. The strategy (or lack thereof) used to draw the clock manifests itself readily, indicating impaired executive function in following a set of rules or organizing and executing a multistep task. When patients finish, they should try copying a clock that the examiner draws in front of them. The numbers 12, 6, 3, and 9 are placed first, and the hands drawn accurately. If construction problems exist, patients have difficulty with the copy task, as well as with the command task. If the copy is good, construction problems may not be a factor in cognitive impairment. There are many standardized, brief mental status tests like these available to clinicians. Routine use of such tests allows for longitudinal assessment and staging of dementia severity.