Global Cognitive Impairment: The Dementias

Steven A. Rogers

Po H. Lu

Jeffrey L. Cummings

I. Principles of dementia and neuropsychiatric symptoms

A. Definitions

Dementia syndromes are defined as acquired disorders of cognitive function, including impairment in memory and at least one other cognitive domain (aphasia, apraxia, agnosia, or executive functioning). These syndromes produce occupational or social disability, represent a significant decline from a previously higher level of functioning, and should not be present exclusively during the course of a delirium (Diagnostic and Statistical Manual of Mental Disorders, 4th edition; [DSM-IV]).
Although neuropsychiatric symptoms are not part of the formal criteria for dementia, they are common in most dementing disorders and play a significant role in the diagnosis, course, severity, and treatment for many types of dementia. Over 90% of those with dementia experience behavioral and psychological symptoms at some point in the course of their illness, with most patients exhibiting a multiplicity of symptoms.

B. Principles of treatment for dementia

In general, the treatment of dementia should follow the American Academy of Neurology’s Practice Parameters for the Management of Dementia (2001), which integrates accurate assessment with pharmacologic and nonpharmacologic interventions.

1. Perform a comprehensive diagnostic evaluation

The purpose of diagnostic evaluation is to identify individuals with the dementia syndrome and distinguish the specific subtype of dementia. Although dementia affects up to 50% of individuals above age 80, it remains undetected by 25% of physicians and 21% of family members.
A dementia evaluation is best performed in the outpatient setting, following the resolution of acute illnesses, delirium, and the treatment of depression. This evaluation starts with a full clinical interview that helps determine the course and symptoms of decline, complicating medical conditions, and presence of significant risk factors (i.e., family history of dementia, substance use, etc.). Considering the possibility of compromised insight, it is recommended that cognitive and functional deficits be substantiated by a care-giver.
Patients should be referred for more extensive neuropsychological assessment that examines general intellectual functioning, attention, language, visuospatial functioning, verbal and visual memory, executive functioning, and mood. Although neuropsychological testing takes a significant amount of time to administer, it can help determine the presence, degree, and pattern of a patient’s cognitive deficits. The actual techniques used to assess these domains are somewhat discretionary, but educational and cultural factors should be considered.
A neurologic exam should assess gait disorders, focal abnormalities, and extrapyramidal signs. Likewise, routine laboratory tests, including blood cell count, glucose level, serum electrolyte level, blood urea nitrogen/creatinine levels, liver and thyroid function tests, syphilis serology, and vitamin B₁₂ and folate levels, are necessary for differential diagnosis and ruling out reversible causes.
Both computed tomography (CT) scan and magnetic resonance imaging (MRI) are recommended for initial diagnostic evaluation to detect structural changes and to assess the level of atrophy in the brain. Although practical considerations of cost and accessibility influence which imaging procedure to use, a noncontrast CT scan is recommended to rule out reversible causes of dementia and the detection of cerebrovascular disease, whereas MRI may be more helpful in differential diagnosis of the types of degenerative dementia. Positron emission tomography (PET) or single proton emission computed tomography (SPECT) scans can identify metabolic and regional perfusion changes that are helpful in differential diagnosis, particularly between Alzheimer disease (AD) and frontotemporal dementia (i.e., hypometabolism or hypoperfusion of the temporal–parietal region and the posterior cingulate is supportive of the former although changes in the frontal and anterior temporal lobes are strongly suggestive of the latter).

2. Implement a biopsychosocial treatment plan

The treatment of dementia is multimodal and guided by the stage of illness and specific symptoms manifested by the patient. Treatment begins with explicit education of family members and caregivers about the diagnosis, prognosis, and options for intervention, including sources of care and support.
The particular type of intervention should involve a combination of pharmacologic interventions and psychosocial treatment for each target symptom. Cognitive and functional losses are typically addressed with cholinesterase inhibitors, vitamin E, and selegiline, whereas psychosis and other neuropsychiatric features are treated with antipsychotics, antidepressants, and other psychopharmacologic medications.
Psychosocial interventions aim to improve quality of life and maximize function through psychotherapy, cognitive remediation, and stimulation therapies (i.e., music, changes in physical environment, pet therapy, etc.).
The actual location of treatment is determined by the need to provide safe and effective interventions in the least restrictive setting. Individuals with dementia who are exhibiting psychotic, affective, or behavioral symptoms may need to be admitted to an inpatient facility. If there is an imbalance between the patient’s clinical status and the caregivers’ability to supervise the patient and manage the burden of care, placement in a long-term care facility should be considered.
Educational programs should be offered to family caregivers to improve caregiver satisfaction and delay the time to nursing home placement. The staff at long-term care facilities should be educated about dementia to minimize the unnecessary use of antipsychotic medications. This education should address basic principles of care, like keeping instructions simple, maintaining consistency and avoiding unnecessary change, and providing frequent reminders.
There is no cure for dementia, but interventions that may significantly affect patient and caregiver quality of life are available. Specific treatment strategies for each type of dementia will be described in the subsequent text.

References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association;1994.

2. Doody RS, Stevens JC, Beck C, et al. Practice parameter: Management of dementia (an evidence-based review). Neurology. 2001;56:1154–1166.

3. LoGiudice D. Dementia: An update to refresh your memory. Intern Med J. 2002;32:535–540.

4. Vicioso BA. Dementia: When is it not Alzheimer disease. Am J Med Sci. 2002;324:84–95.

II. Types of dementia

A. Alzheimer disease

1. Clinical background and prevalence

Alzheimer disease is the most common form of dementia in the elderly, occurring in 6% of the population above age 65 and increasing by a factor of two with every 5 years of age after age 60.
The onset generally occurs between ages 40 and 90, although most patients develop it after age 65. The average duration of the disease can vary from 5 to 20 years, and once acquired, it reduces life expectancy by half.
Age is the primary risk factor for developing AD, although there is a slightly higher susceptibility for women, African Americans, and those with a history of head trauma and lower educational achievement. It is not certain why women may be at greater risk, although some researchers have posited a relationship between AD and hormonal imbalances. The increased risk in African Americans may be due to their vulnerability to vascular conditions. Individuals with head injury or lower education may have less cognitive reserve and a lower threshold for developing cognitive impairment.
Genetically, AD is complex, heterogeneous, and follows an age-related dichotomy. Early onset familial AD, which typically presents before age 65, represents only a small fraction of all patients with AD (<5%) and is transmitted in an autosomal dominant fashion. Late-onset (“sporadic”) AD (age 65 or older and represents most AD cases) follows the common disease/common variant hypothesis, which postulates that common disorders are governed by common deoxyribonucleic acid (DNA) variants that increase disease risk, but are insufficient to cause a specific disorder. Those with the apolipoprotein e4 (ApoE-4) are at a genetic risk for developing AD. The presence of even one copy of the ApoE-4 genotype may account for as much as 50% of the risk for developing AD, with increased risk as the number of allele copies increase. To date, only the e4 allele of the apolipoprotein E gene has been established as such a DNA variant, carrying a threefold risk for AD.

2. Pathophysiology

The histopathologic hallmarks of AD include extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal and synaptic loss.
The putative process by which these features lead to dementia has been unified under the amyloid cascade hypothesis. The amyloid precursor protein (APP) is cleaved by β and γ secretase, leading to the production of β-amyloid peptides that are transported extracellularly and undergo an abnormal accrual and misfolding that leads to aggregation into amyloid or neuritic plaques. In turn, this triggers a succession of events including abnormal tau protein phosphorylation and formation of neurofibrillary tangles, inflammation, oxidation, glutamatergic excitotoxicity, and loss of neurons, all of which further exacerbate the pathogenic process and lead to cell death. These latter processes have all been implicated in the pathophysiology of AD but are considered secondary consequences of the generation and deposition of Aβ.
Neurochemical deficits in acetylcholine, norepinephrine, and serotonin, which are altered through the neurohistologic changes in the neurons and synapses, have been implicated most in the neuropsychiatric symptoms of AD. In particular, the apathy, agitation, and depression seen in AD may be partially attributed to the cholinergic–serotonergic imbalance and other alterations in the brain biochemistry.

3. Diagnosis

Once individuals present with symptoms of cognitive impairment, diagnosis of AD is based on the criteria established by the National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association.

Definite AD is diagnosed when a prior clinical diagnosis of probable AD is confirmed by autopsy or biopsy.
A diagnosis of Probable AD is made when there is no histopathologic confirmation available but individuals meet all clinical criteria for AD. Individuals must have gradually progressive deficits in memory and one other cognitive area, onset between ages 40 and 90, and the absence of delirium or other disorders that might account for the cognitive deficits.
Possible AD is diagnosed when there is a gradually progressive cognitive deficit in one area without any other identifiable cause, or there is a complicating illness that could account for the dementia syndrome.

4. Neuropsychiatric symptoms

More than 80% of patients with AD manifest neuropsychiatric symptoms, with apathy, depression, and agitation/aggression being the most common abnormalities.
The apathy of AD is characterized by a lack of interest in formerly pleasant activities, reduced excitement for social activities, and a loss of social engagement and intimacy (see Chapter 1).
Depression seems to develop early and persist throughout the course of AD. Some researchers suggest that depression is a prodromal risk factor that heralds the onset of AD, whereas others contend that depression is an early symptom that declines as insight becomes compromised (see Chapter 5).
Symptoms of agitation/aggression are most prevalent during the middle and later stages.
Psychotic symptoms seem to operate in a quadratic relationship with disease stage, occurring primarily during the early and late stages of AD (see Chapter 7). Typical delusions include erroneous beliefs that others are stealing from them, delusions of infidelity, and beliefs consistent with Capgras syndrome.

5. Treatment

a. Cholinesterase inhibitors

Cholinesterase inhibitors are the approved pharmacologic interventions for mild-to-moderate stages of AD and the first treatments approved by the U.S. Food and Drug Administration (FDA) for treatment of AD. Their mode of action is not to modify the progression of the disease, but rather to address the symptoms of AD by inhibiting the destruction of intrasynaptic acetylcholine, which increases the amount of acetylcholine available for neurotransmission.
Currently, the four FDA-approved cholinesterase inhibitors are tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon). Owing to its hepatotoxic effects, tacrine is now rarely used. Even though the remaining three drugs differ in some pharmacologic aspects, double-blind, randomized controlled trials show how they have similar effects in improving global function and enhancing cognitive and behavioral functioning among individuals with AD.
Donepezil is a pure acetylcholinesterase inhibitor. It has a half-life of 70 hours, and it is typically initiated at a dose of 5 mg daily and increased to 10 mg daily after 1 month. A review of 13 double-blind, randomized trials comparing donepezil to placebo, found a significant beneficial effect of donepezil on cognitive functioning, global status, and activities of daily living for patients with mild or moderate AD after 12, 24, and 52 weeks. Similarly, a review of seven double-blind, randomized controlled trials revealed significantly improved cognition, reduced loss of activities of daily living, improved quality of life, and delayed nursing home placement among those prescribed donepezil compared with placebo. Treatment with donepezil appears to reduce symptoms of agitation and behavioral disturbance among those with moderate-to-severe AD. The primary side effects include gastrointestinal problems, nausea, vomiting, and diarrhea.
Galantamine has two modes of action, namely inhibiting acetylcholinesterase and modulating allosteric nicotinic receptors. Modulation of nicotinic receptors increases the release of acetylcholine and stimulates the release of other neurotransmitters responsible for cognition. Two doses of 4 mg each are required daily due to its short half-life (5 hours), and this dosage is increased to 8 mg twice daily after 1 month. The extended release (Razadyne ER) formulation is administered once daily. On the basis of the review of six double-blind, randomized, controlled trials, patients with AD who received treatment with galantamine exhibited significantly better performances on cognition, global functioning, and behavioral measures compared with individuals receiving placebo. After 12 months of treatment with galantamine, most patients are 4.7 points better on the Alzheimer Disease Assessment Scale (ADAS-cog/11) than those who receive placebo, which suggests significant improvement in cognitive functioning. Potential side effects include nausea, diarrhea, and vomiting.
Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase. It is initiated at 1.5 mg twice daily and is eventually increased to 4.5 mg twice daily after 2 months. Compared with the other two cholinesterase inhibitors, rivastigmine tends to have more side effects. These include weight loss, nausea, and vomiting. However, it has beneficial effects on cognition, global functioning, activities of daily living, and the control and prevention of abnormal behaviors. When taken for a year, it significantly reduces cognitive decline compared with placebo. It appears to delay patients’overall global impairment, even after 5 years of treatment.
All three cholinesterase inhibitors show similarly positive effects on cognition, global functioning, and activities of living, such that studies directly comparing these medications did not reveal significant differences in efficacy. The process of selection is one of considering the patient’s optimal dosing schedule, the physician’s familiarity with the agents, and the patient’s preferences.

b. Memantine

Memantine has more recently emerged as an effective pharmacologic intervention for the moderate-to-severe stages of AD.
Memantine is posited to interfere with glutamatergic excitotoxicity. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) and subserves neurotransmission and plasticity. An extracellular increase in glutamate may excessively activate N-methyl-D-aspartate (NMDA) receptors, one subtype of glutamate receptors, and lead to intracellular accumulation of calcium that can initiate neuronal death cascades. Without blocking the physiologic activation of the NMDA receptor, memantine blocks the neural activity of prolonged glutamate release.
Studies of memantine consistently reveal a beneficial effect on cognition, activities of daily living, and behavior for those with moderate-to-severe AD. Most common side affects are headache, dizziness, falls, somnolence, and confusion.
Most individuals begin at 5 mg per day and increase the dose at weekly intervals until they reach the target dose of 10 mg twice daily.

c. Antioxidants (vitamin E and selegiline)

Vitamin E and selegiline have recently emerged as potentially disease-modifying agents in the treatment of AD. In placebo-controlled, double-blind, multicenter trials, both the independent and combined effect of these agents delayed functional deterioration, nursing home placement, loss of activities of daily living, and progression to severe dementia in patients with moderate AD.
Vitamin E is typically given at 2,000 units daily, and selegiline is administered at 5 to 10 mg per day. Their mechanism of action appears to protect lipids against oxidative stress and slow nerve cell damage, including damage associated with amyloid deposition.
Selegiline may result in orthostatic hypotension as a side effect, but the low toxicity of both vitamin E and selegiline suggests that they may be useful agents in delaying the progression of disease among those in the moderate stages of AD.

All the cholinesterase inhibitors are of equal efficacy; choosing the medication depends greatly on the agent that the clinician is most familiar with. There are more side effects with rivastigmine; these can usually be managed by giving the agent with food and titrating slowly (increase by 1.5 mg b.i.d. every month). Patients are treated long term and discontinuation is considered when the physician and the family believe that the disease is so severe that a meaningful response is no longer likely. Any deterioration during the withdrawal period—functional, cognitive, behavioral—is evidence of continuing benefit, and the medication should be reinstated. Withdrawal is conducted by administering half the usual starting dose for 1 week and then stopping the agent.

d. Psychosocial approaches

To the extent possible, these pharmacologic treatments should be paired with psychosocial interventions. Activity programs, changes in patients’physical environment, exposure to music and massage, and greater education for caregivers have all been associated with improvement in functional symptoms and mobilization of the patients’cognitive resources.
Behavior therapy and reminiscence therapy may help patients with AD adjust to their illness, reduce problem behaviors, and foster slight gains in mood and cognition. However, it is critical to match the level of therapeutic demand with patients’.

References

1. Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest. 2005;115:1449–1457.

2. Birks J, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2003;3:1–96.

3. Cummings JL. The neuropsychiatry of Alzheimer’s disease and related dementias. Independence, KY: Taylor & Francis;2003.

4. Cummings JL. Alzheimer’s disease. N Engl J Med. 2004;351:56–67.

5. Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer’s disease. Neurology. 2005;64:34–39.

6. Loy C, Schneider L. Galantamine for Alzheimer’s disease (Review). Cochrane Database Syst Rev. 2004; 4:1–71.

7. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: Report of the NNCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;39:939–944.

8. Potyk D. Treatments for Alzheimer disease. South Med J. 2005;98(6):628–635.

B. Vascular dementia

1. Clinical background and prevalence

Vascular dementia (VaD) is the second most common form of dementia. It occurs in 10% to 20% of patients with dementia and represents a constellation of cognitive and behavioral symptoms that are caused by cerebrovascular disease.
The survival rates are generally worse compared with AD, and unlike the insidious onset and gradual progression of AD, VaD usually involves a relatively sudden onset and subsequent stepwise progression in cognitive decline.
The primary risk factors for VaD are history of prior strokes, hypertension, diabetes, coronary artery disease and hyperlipidemia. Older African Americans may be at a slightly higher risk due to their high risk for stroke, and unlike AD, men are more likely to develop VaD than women.

2. Pathophysiology

Cerebrovascular disease leads to either cortical or subcortical injury. Large vessel cerebrovascular disease and cardiac embolic events commonly contribute to multiple cortical infarcts and strategic-infarct dementias, whereas subcortical (small-vessel) disease, which usually results from hypertension and diabetes, produces periventricular white matter ischemia and lacunar strokes.
Hypertension and diabetes represent risk factors for athero-sclerosis of the small arterioles in the subcortical region and connections with the frontal lobe. MRI can differentiate the types of VaD and identify involved structures.

3. Diagnosis

Diagnosis of VaD depends on evidence of cerebrovascular disease, signs of stroke on clinical observation and neuroimaging, and a compelling temporal relationship between cognitive symptoms and the cerebrovascular event. This relationship is regarded as present if the dementia developed within 3 months of a stroke, or if there was abrupt deterioration or fluctuation in the progression of cognitive function.
The cerebrovascular insult is often heterogeneous, such that three primary subtypes have been described: (a) Cortical (multi-infarct) dementia, (b) subcortical (small-vessel) dementia, and (c) strategic-infarct dementia.
The diagnosis of VaD is complicated by the high prevalence of vascular lesions in patients diagnosed with AD. This comorbidity has led to the construct of mixed dementia, where AD is complicated by the presence of cerebrovascular disease. When there is a mixed presentation of AD-type pathology and cerebrovascular symptoms, there may be cognitive decline before stroke, the course of decline may be insidious between strokes, and the phenotype includes the features of AD. This represents a distinct syndrome with unique clinical and neuropsychiatric features.

4. Neuropsychiatric symptoms

Depression is the hallmark neuropsychiatric symptom of VaD. This syndrome is partially due to the disruption of frontal-subcortical circuits that mediate disturbances in behavior and mood (see Chapter 5).
Apathy and aggression may also occur among those with VaD (see Chapter 1); psychosis and disinhibition are less common (see Chapter 7).
Deficits in cholinergic transmission, including abnormalities in nicotinic receptor binding, may contribute to the development of cognitive and neuropsychiatric impairment in VaD. This outcome is largely because cholinergic structures are vulnerable to ischemic damage.

5. Treatment

The primary area of management for VaD is the prevention of cerebrovascular injury. Antiplatelet medications, such as 50 to 325 mg daily dose of aspirin, are the most widely used agents to prevent the recurrence of stroke. They also stabilize cognitive test performance and slow cognitive decline.
There is no FDA-approved treatment for the cognitive and behavioral features of VaD, hence prescribing cholinesterase inhibitors is off label, but there are data from controlled trials supporting the use of these agents in other disorders with cholinergic deficits including VaD, in conjunction with management of cerebrovascular risk factors. Among patients with VaD, treatment with galantamine is associated with improved cognition, functional ability, and behavior. Similarly, those with VaD show slowed cognitive decline after taking rivastigmine. Trials using donepezil as a treatment for VaD reveal greater cognitive improvements after 5 months than those receiving placebo. The approach in starting and stopping cholinesterase inhibitors for VaD is the same as that for AD but these agents have cardiac effects and should be used with special caution in this population of patients.
Memantine also had a beneficial effect on cognition, behavior, and the reduction of agitation among individuals in trials with VaD.
A combination of vitamin E and C supplements may be associated with an 88% reduction in VaD frequency and the promotion of cognitive performance. Therefore, vitamins E and C may have a protective effect against the cerebrovascular injuries that lead to VaD, perhaps by inhibiting platelet aggregation and modulating immune responses.
Speech and language therapy can significantly benefit those with aphasia and dysarthria, just as physical therapy can provide gait retraining.
The methods of primary prevention against VaD include management of hypertension, stroke prevention, reduced stress, healthy diet (reduced low-density lipoprotein cholesterols), and a minimum of 8 hours of sleep. It also requires limiting stress, stopping smoking, and moderating one’s consumption of alcohol or illicit substances.

References

1. Erkinjuntti T. Cognitive decline and treatment options for patients with vascular dementia. Acta Neurologica Scandinavica. 2002;106:15.

2. Erkinjuntti T, Kurz A, Small GW, et al. An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia. Clin Ther. 2003;25:1765–1782.

3. Erkinjuntti T, Rockwood K. Vascular dementia. Semin Clin Neuropsychiatry. 2003;8(1):37–45.

4. Nyenhuis DL, Gorelick PB. Vascular dementia: A contemporary review of epidemiology, diagnosis, prevention, and treatment. J Am Geriatr Soc. 1998;46(11):1–22.

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6. Small GW, Erkinjuntti T, Kurz A, et al. Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer’s disease with cerebrovascular disease. CNS Drugs. 2003;17(12):905–914.

C. Parkinsonian syndromes

(see Chapter 9) The parkinsonian syndromes are a heterogeneous group of degenerative neurologic disorders that include symptoms of parkinsonism, often with additional or atypical clinical features (Mendez and Cummings, 2003; Mitra et al. 2003). The most common are Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

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