Delirium and Dementia

Disease/ Disorder

Definition

Delirium, an acute confusional state, is a clinical syndrome characterized by fluctuating attention and confusion. It can develop quickly, over hours to days, and its duration is highly variable. Delirium can present with hypoactive, hyperactive, or mixed states. It can be triggered by medication, physiologic or psychologic stress, or illness. Delirium is generally reversible with treatment of the precipitating factor, but some chronic cases have been identified. Longer duration is directly associated with worse short and long-term outcomes. Delirium is common, although far from normal, in older adults. It is more common in individuals who also have dementia. ^1,2

Dementia is an acquired, gradual loss of memory and cognitive function. It characteristically includes impairment of major cognitive domains, such as language, visual perception, and executive function. The cognitive impairment is not attributable to any other cognitive disorder.³

Mild cognitive impairment (MCI) is characterized by a decline in memory or other cognitive domains while overall function is relatively preserved. That is, there is objective impairment in one or more cognitive domains while there are no significant impairments in instrumental activities or daily living. No features of global cognitive impairment are present. Older adults with MCI are at increased risk for progression to dementia. Individuals with MCI and other risk factors for dementia require close monitoring.⁴

Etiology

Delirium’s common triggers include:

• Patient: age 65 years and older; pre-existing cognitive deficits; severity of medical comorbidities; previous episodes; perioperative status.
• Medical/surgical: infection; burns; acquired immune deficiency disease; fracture, particularly hip fracture; fluid and electrolyte imbalance; organ failure such as cardiac, liver and renal; infection; pain; metabolic causes; immobilization; hypothermia; neurological problem such as acute stroke.
• Pharmacological: polypharmacy; drug/alcohol use; drug/alcohol withdrawal. Medications that are on the list of Beers Criteria due to high potential for causing confusion are likely to be triggers. These include benzodiazepines, anticholinergic agents, opioids, anticonvulsants, lithium, corticosteroids, histamine-2 blockers.
• Environmental: unfamiliar environment; lack of social interaction; lack of stimulation or orientation cues.
• Psychosocial: psychological or social stressors.²

Dementia Etiology and pathophysiology vary with dementia type:

• Alzheimer’s Disease (AD), which accounts for more than 70% of dementia diagnoses, involves abnormal conformation and deposit of tau protein and beta amyloid in neurofibrillary tangles and plaques. These deposits, which affect brain areas including hippocampus, parieto-temporal neocortex, and related connections, interrupt cortical functioning^.  
• Vascular dementia, which accounts for at least 15-20% of dementias and likely contributes to others as well, is associated with cerebrovascular disease.
• Lewy body dementia (LBD), which compromises roughly 5% of all dementia cases, involves deposition of alpha synuclein in the cortex and subcortex of the brain.⁵
• Other dementias, which account for about 5% of total cases, include frontotemporal dementia, which involves abnormal deposition of tau protein.⁶
• Rarer entities include dementia associated with Huntington’s disease and prion diseases like Creutzfeldt Jakob Disease.⁵

Mild cognitive impairment

The etiology is likely very similar to dementia.

Epidemiology including risk factors and primary prevention

Delirium

Delirium is the most common complication of hospitalization for older adults. It occurs in all areas of the hospital, from the emergency department to intensive care units. It has been noted in more than 50% of older adults who have had surgeries such as hip or vascular procedures. In general medical units, its prevalence is estimated to be up to 30%. It affects about 15% of older adults in long-term care settings.^7,8

Specific factors that tend to put patients at more risk for delirium include absence of clock, hearing aids or glasses; physical and chemical restraints; change in location within hospital; acute illness; and physical and environmental stressors.^7,8 Since the start of the pandemic, delirium has been seen in the setting of severe COVID-19 infection. Up to roughly 55% of patients in ICUs develop delirium during their hospitalization.⁹

Primary prevention measures include identifying patients who are at risk for delirium and modifying environments to optimize orientation and normal sleep-wake cycles.

Medications with high potential to cause delirium should be used with caution. Underlying conditions should be treated promptly.⁷

Dementia

Dementia affects approximately 20% of individuals over 80 years of age. As more people reach older age, the prevalence of symptomatic neurodegenerative diseases will likely increase substantially.⁵

AD risk factors include advancing age, especially over 85; first degree relatives with onset under the age of 65; apolipoprotein-e4 gene; female gender, history of severe traumatic brain injury or multiple repetitive injuries; cerebrovascular disease, homocysteinemia; and low level of education.¹⁰ Protective factors for AD may include use of nonsteroidal anti-inflammatory drugs, moderate intake of wine, coffee, and regular exercise.¹¹

For other dementias, risk factors and primary prevention measures include:

• Vascular dementia: risk factors include hypertension, hyperlipidemia and diabetes mellitus. Primary prevention measures include treating these conditions.
• Lewy body dementia (LBD) is associated with Parkinson’s disease (PD) and may also occur on its own. It is possible that treatments for PD have an effect in preventing LBD.
• Huntington’s disease occurs as a result of a genetic abnormality (CAG trinucleotide repeat) that is inherited in an autosomal dominant pattern. Affected individuals generally display some behavioral and motor abnormalities in their thirties or forties. Symptoms tend to progress from there.
• Prion disease, such as Creutzfeldt Jakob, is contracted. One possible source of transmission is through brain tissue of sheep and cows. Prevention methods have not been definitively established.^3,5

Mild cognitive impairment is estimated to occur in more than 10% of individuals over 70 and 20% of individuals over 80. Primary prevention is similar to the paradigm for dementia in general. This includes treating vascular risk factors and other illnesses, staying cognitively active, and maintaining a program of physical activity over time.¹²

Patho-anatomy/physiology

Delirium

Delirium can be thought of as a type of acute brain failure. Its pathophysiology may include any factor that interferes with the brain’s homeostasis. Some factors that have been identified and postulated include abnormally active proinflammatory cytokines, oxygen deprivation, sleep-wake cycle abnormalities, and dysregulation of the limbic-hypothalamic-pituitary-adrenal axis. Neurotransmitter abnormalities, such as acetylcholine deficiency; excess dopamine, glutamate, or norepinephrine; and decreased or increased serotonin levels, can also contribute to problems. Lastly, alterations in activity of drug-metabolizing enzymes may explain the unexpected toxicity and adverse effects of otherwise benign medications.⁸

Dementia

Abnormal processing or deposition of proteins results in inflammation and cell destruction. The involved proteins vary by type of dementia. Cerebral blood vessels abnormalities negatively affect blood flow through the brain. Neurons both die and become dysfunctional. Communication between neurons and neuronal networks is damaged or lost. Functional sequelae follow.¹²

Mild cognitive impairment

The pathophysiology is likely similar to what occurs in dementia.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Delirium:

• Acute/ subacute: At least 50% of affected individuals are improved and back to their baseline one month after developing delirium. Others tend to recover over the next 1 to 3 months.
• Chronic/stable: There are some cases, as many as 10%, where delirium never fully clears, and cognitive impairment is noted over the subsequent long-term. It is not yet clear why some individuals do not recover.^7,8

Dementia

Memory impairment is usually followed by decline in language and visuospatial skills, then executive functions. Neuropsychiatric sequelae such as behavior and personality changes, often. Speech and swallowing issues can occur. Impairments in other aspects of function progress, often in parallel to the cognitive changes. These changes generally occur over 5 to 10 years in AD and LBD, with shorter courses for other dementias, but these durations are highly variable in individual cases.³

Mild cognitive impairment

Each year, an estimated 10 to 15% of people with MCI progress to dementia. MCI also has a strong association with depression. At least 33% of people with MCI also have depression. It is not yet clear whether the relationship between MCI and depression represents some disease progression or simply an association.⁴

This table provides a basic summary of the stages of dementia and mild cognitive impairment.

DEMENTIA	MILD	MODERATE	SEVERE	END STAGE
MEMORY LOSS	Short term	Most short term and some long term	Most short and long term	Almost all short and long term
FUNCTIONAL LOSS	Instrumental activities of daily living (IADLs)	Most IADLs and some basic activities of daily living (ADLs)	Basic ADLs	Dependent for all activities

Essentials of Assessment

History

Delirium

History and physical examination play instrumental roles in the diagnosis and assessment of delirium. The patient’s current mental status should be compared to their reported baseline. Potential causes such as illnesses, treatments, and interventions should be thoroughly explored. Information about nutrition, bowel/ bladder, hydration status, recent sleep and activity patterns can be crucial.⁸

Dementia

Other conditions may mimic dementia. These problems, which can include vitamin deficiencies (B1, B12, folate and niacin), anemia, endocrinopathies involving thyroid or adrenal function, medication toxicities, and paraneoplastic phenomena, can reverse with treatment after they are identified. Effective history and assessment are essential.

History should include discussion of possible subtle functional changes. These can include forgetting appointments, problems with finances, misplacing common objects in odd places, and driving or kitchen mishaps. Generally, patients and families will note a history of progressive memory impairment, followed by impairments in language and visuospatial functioning. Patients may develop inability to recognize faces (prosopagnosia) and objects (visual agnosia), although they may not be aware of the problem. Neuropsychiatric and behavioral changes, which can be most burdensome to families, often follow.^3,13

MCI

The history for suspected MCI is similar to that for dementia.

Overlap with depression

Of note, mild cognitive impairment and dementia can have symptoms that overlap markedly with depression. Nearly a third of people with MCI also have depression. Individuals who have been diagnosed with dementia may have depression that mimics dementia, a condition termed pseudodementia. It is possible for individuals to be misdiagnosed with MCI or dementia when they actually have depression. It is also possible for MCI or dementia to co-exist with depression. The depression may well make cognitive symptoms seem worse.⁴

For both MCI and dementia, thorough screening for depression is warranted. The Geriatric Depression Scale is one useful tool. Careful history, with focus on symptoms of depression, is also valuable. Common symptoms of depression include difficulty sleeping, lack of interest in activities, change in appetite, feeling sad, feeling guilty, difficulty concentrating, thoughts of suicide. Consultation with a psychiatrist or neuropsychologist can be helpful in this complex diagnostic process.¹⁴

Physical examination

In cases of suspected delirium, dementia and MCI, a comprehensive physical exam is warranted. Clinicians should pay particular attention to these potential issues, which may either affect the assessment or be cause for additional evaluation:

• Nutritional status
• Any evidence of self or caregiver neglect.
• Visual and hearing problems which may inadvertently affect cognitive evaluation.
• New illness/acute exacerbation of chronic diseases.
• Focal neurological signs or symptoms which can herald an underlying abnormality in the brain.¹³

Functional assessment

Delirium

Clinicians should assess for these delirium-specific functional factors:

• Recent development of fluctuating confusion.
• Disturbance of consciousness.
• Changes in cognition.
• Underlying medical condition.

Assessment needs to include a determination of which subtype of delirium is occurring:

• Hyperactive: hallucinations, delusions, agitation and disorientation.
• Hypoactive: lethargy, apathy, sleepiness, decreased interest and motivation.
• Mixed: features of hyperactive and hypoactive at different times.

Functional assessment includes evaluation of current ability to complete activities and instrumental activities of daily living. Clinicians should also focus on ways to keep delirious individuals safe from harm.^1,7,8

Dementia

Cognitive assessment tools, such as the Mini-Mental State Examination (MMSE), can prognosticate impairment and functional decline.  Functional issues, particularly psycho-behavioral changes, can have the biggest impact on caregivers and the need for institutionalization. Functional assessment, then, is of paramount importance. The following table illustrates the common progression as function is lost during dementia:³

AD	MMSE Score	Impairment	Functional help needed	Caregiver Roles
MILD	20 – 26	Short-term recall	Mild functional dependence	Assisting with IADLs such as finances
MODERATE	10 – 20	Remote memory impairment	Moderate dependence, especially with hygiene/ ADLs	Driving, shopping
SEVERE	< 10	Gait and balance impairment, incontinence, myoclonus	Total mobility dependence	Constant supervision for all activities

Laboratory studies

These are performed to exclude other diagnoses, even concurrent ones, that may be reversible. Studies include complete blood count; electrolytes; renal, liver and thyroid function tests; C-reactive protein; folate; B12, calcium; glucose; serologies (syphilis, Lyme); oxygen-hemoglobin saturation; urinalysis; urine and blood cultures.^3,13

Imaging

Imaging can have a role in excluding other conditions as well as confirming diagnosis.

• Imaging (e.g., chest radiograph) explores medical causes (e.g., pneumonia) of delirium.
• Brain imaging is used to look for other diseases causing cognitive impairment (cerebral infarct/hemorrhage, encephalomalacia from a prior injury, or tumor).
• Amyloid deposition in the brain can be detected by positron emission tomography (PET).
• Single photon emission computed tomography (SPECT) and PET scanning may be able to differentiate dementias. This will likely become more useful in future years, as imaging techniques advance.¹³

Supplemental assessment tools

Delirium

Standardized assessments are used to differentiate delirium from other conditions and to track symptom severity over time. Some tools that are commonly used include:

• The Confusion Assessment Method (CAM) is a widely used screening tool that was developed to diagnose delirium in older adults.  It has a sensitivity of nearly 94% and positive predictive value for delirium detection of over 90%.¹⁵
• The Delirium Rating Scale (DRS-R-98) both assesses symptom severity and has diagnostic significance. It can classify symptoms as relating to cognition or not. This can help distinguish delirium from dementia, schizophrenia, depression or medical illness. With a sensitivity and sensitivity above 90%, this tool can help helpful.¹⁶
• The Memorial Delirium Assessment Scale (MDAS) can measure and track the severity of delirium. It assesses changes in level of arousal, cognitive function, and psychomotor activity over time. It can even be used to track changes over the course of a single day. Since scores differ between patients with and without delirium, it can also help with diagnostic issues.¹⁶
• The Delirium Observation Scale is a 25-point scale used to recognize delirium during regular nursing care. This screening tool has a sensitivity of 90% and a specificity of 92%.¹⁷
• The Informant Questionnaire on Cognitive Decline in Elderly (IQCODE) allows caregivers to provide information about 25 everyday activities. It correlates with MMSE scores.¹⁶

Dementia

• The Mini Mental State Exam (MMSE) remains in widespread use. Confounders to its use include language fluency and education level.
• Another commonly used test is the Mini-Cog Assessment Instrument. This has high sensitivity, is time-efficient and not confounded by level of education and native language. It involves repeating three words immediately after presentation; clock drawing; and retrieving the three words presented above. A score of 2 or less (maximum 5) screens positively for dementia.
• A battery of neuropsychological tests is often helpful in clarifying the dementia diagnosis. These tests can be particularly valuable when there are questions about the type of dementia.¹⁴

Mild Cognitive Impairment

• The Montreal Cognitive Assessment (MoCA) can effectively screen for MCI. It assesses cognitive domains including short term memory recall, visuospatial abilities, and executive functions such as orientation, language and phonemic fluency, verbal abstraction, sustained attention, attention, concentration and working memory. The MoCA’s sensitivity and specificity for detecting MCI have been reported to be 81.2% and 73% respectively.¹⁸

Environmental Assessment

Delirium

An environmental assessment is warranted. The healthcare environment can be unfriendly to an older adult’s cognition. Sleep deprivation, lack of orientation, nighttime noise, absence of natural light, inconsistent staff and unfamiliar food can be factors in development or prolongation of delirium. These and other factors can also be anticipated and addressed before they cause significant problems.

Dementia

It is important to assess the patient’s living environment. Safety can be enhanced by items like wearable alarm systems and supervision around appliances. Assistive devices and falls prevention measures may also be useful.

Social role and social support system

Mild-to-moderate dementias usually can be managed at home but will likely require a caregiver. Family caregivers need to be assessed for caregiver burden and stress issues, since these can affect their ability to be effective caregivers.

Professional Issues

As dementia progresses, movement to an alternative living setting may be necessary. Some individuals and families prefer to stay at home with help, while others may choose to go to another care setting. Options include adult day health care, assisted living, and subacute care/ nursing home environments. Clinicians can help families through these transitions.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Delirium

• Treatment strategies for delirium:
  • Interdisciplinary teams conduct environmental rounds to detect and address the presence of common triggers.
  • Physiologic precipitants should be treated promptly, with minimal use of medications with anticholinergic effects.
  • Oxygen status, hydration and nutritional status should be optimized.
  • The patient should be mobilized.¹⁹
• Using medications in delirium:
  • Clinicians working with older adults should keep medications to a minimum. When medications are indicated, clinicians should start at low doses and titrate up slowly.
  • Medications which have high potential to cause confusion and other adverse effects should not be first line choices.
  • Medications that may be useful if environmental measures are not sufficient in cases of acute delirium:
    • Haloperidol, a first-generation dopamine antagonist, may be used in a short course to treat severe, acute, delirium-related agitation. However, its benefit has not been consistently demonstrated and its use is limited by medication interactions and its potential to cause prolonged QT interval and extrapyramidal effects.
    • A recent meta-analysis has found insufficient data to show that second-generation antipsychotics, such as quetiapine, have a superior effect on dementia outcomes in comparison to haloperidol. Additionally, harmful cardiac effects may be observed more frequently with second-generation medications.²⁰

Dementia

• Treatment options for Alzheimer’s dementia: There are three approved classes of medications. The optimal time to start these medications or recommended duration of treatment are not yet known for certain.
  • Acetylcholinesterase inhibitors are thought to work by increasing the amount of acetylcholine available to mediate learning and memory. Examples include donepezil, rivastigmine, and galantamine.¹⁰
  • N-Methyl-D-Aspartate (NMDA) receptor antagonists are believed to block glutamate-mediated excitotoxicity and associated calcium overload, mitochondrial dysfunction, abnormal oxidation, and neuronal apoptosis. One example, memantine, has been shown to have some benefit on cognition, particularly in moderate to severe cases of AD.¹³
  • Aducanumab is a monoclonal antibody medication. It was approved by the FDA for the treatment of Alzheimer’s Disease on 6/7/2021.²¹ This medication has been shown to decrease the level of beta-amyloid plaques observed on PET scan imaging. However, it is very expensive. Its approval remains controversial, and studies regarding its use have not consistently demonstrated clinical benefit and its potential risks, which may include intracerebral hemorrhage, are not yet fully known.²²
• Dementia-related psychosis: Antipsychotic agents are not routinely recommended for treatment of dementia-related psychosis since these agents are associated with an increased risk of stroke, heart failure, and death.²⁰
• Therapies in dementia:
  • Occupational therapy, speech therapy, and other forms of cognitive rehabilitation may be helpful to address short term problems. Patients and families can benefit from recommendations regarding ways to optimize medication adherence and home safety. Adaptive equipment, including cognitive orthotic devices and smartphone applications which can compensate for some cognitive impairments, can also be implemented as indicated. A course of cognitive stimulation may also be beneficial. The optimal timing, paradigm of treatment, and long-term effects have not yet been established.²³
  • Speech therapy can be helpful for individuals who develop dysphagia. Speech therapists can assess swallowing abilities. Food and liquid consistencies may need to be altered to prevent aspiration, optimize safety, and still allow for pleasurable mealtimes. For instance, individuals with cognitive difficulties can benefit from thickened liquids or softer foods. A dietician can provide recommendations for appropriate foods and drinks within the restrictions outlined by the speech therapist.
  • Exercise
    • Exercise, in the form of regular physical activity, may be protective against cognitive impairment. Multiple studies suggest that there are significant benefits of long-term, regular exercise on cognition and dementia risk. Aerobic exercise has the potential to decrease cerebral atherosclerosis effects and resultant negative effects on brain health.
    • In patients with mild cognitive impairment and dementia, programs of sustained exercise over 1 to 12 months have been associated with cognitive improvements.  Patients who engage in aerobic exercise can have fewer new cognitive problems, less or slower cognitive decline, and improved overall function.
    • The physiology behind the benefits of exercise may involve bolstering of structures including gray matter and hippocampal structures, better connectivity of neural networks, or effects of increased cerebral oxygenation in settings of better cardiovascular fitness. Some of exercise’s myriad other benefits include decreased osteoporosis and fracture risk, improvements in depression and anxiety, and decreased overall mortality risk.Clinicians should take individual patients’ needs into account when recommending exercise programs. The risk for possible adverse effects, including falls and acute coronary issues, should be minimized. In general, it seems reasonable and appropriate, based on available information, to recommend aerobic exercise that increases the heart rate, for 20 to 30 minutes per session, at least 3 days per week. The intensity should be individualized based on the person’s status and abilities. ^{12, 24}
    • Resistance training also appears to slow cognitive decline and may lead to lower white matter atrophy and lesions. The optimal regimen is not yet known.  Additional investigations on the effect of resistance training on dementia are needed.²⁵
    • Adapted interventions, such as participating in aerobic exercise with the assistance of a cane or wheelchair, have not been extensively studied. Clinicians may recommend adapted activities by extracting information from available literature. A key concept is that aerobic activities, and some resistance training, likely to have a positive effect on cognitive function over time.
  • Nutrition
    • Available evidence suggests that consumption of fruits and vegetables can have benefits for brain health. It is also possible that a well-balanced diet, including low amounts of highly processed foods,  can help protect against development of dementia. This link is likely indirect, as in preventing conditions, such as diabetes, that are then risk factors for dementia. Standardized recommendations are not available, but it is likely that optimizing nutrition can be beneficial.  
    • Recommended Daily Allowances (RDAs) provide guidelines for optimal intake of vitamins and micronutrients. Clinicians should encourage individuals to meet their RDAs to avoid nutritional deficiencies and potential sequelae on brain health and function.
    • A significant relationship has been shown between severe vitamin D deficiency and risk of developing dementia.
    • Vitamin B12 deficiency may also lead to the development of dementia. While current evidence on vitamin B12 supplementation has not shown to improve cognitive performance in the elderly, additional research is needed to explore the effect of vitamin B12 supplementation on dementia.²⁶
    • Individuals with cognitive impairment may develop declines in nutritional intake as their cognition worsens. Sequalae can include unintentional weight loss, malnutrition, and increased morbidity and mortality. Environmental interventions, such as buffet-style and family-style meals, and pleasant music at mealtimes, may help attenuate this problem.

MCI generally does not require medical treatment. It is not yet clear whether and how cognitive interventions may help MCI, but regular physical activity is likely beneficial.⁴

At different disease stages

Delirium:

The treatment paradigm does not significantly change in prolonged courses compared to the acute phase.

Dementia:

• Individualized general and specific interventions help the patient and family optimize safety and enhance physical and emotional well-being.
• Patients, family members and other caregivers, and clinicians often need to address difficult situations as cognition worsens. Physical and sensory limitations and neuropsychiatric symptoms may also develop. Individuals may lose their ability to manage finances or other instrumental activities of daily living.
• Caregivers may need to assist with financial matters. Caregivers may need to enlist legal assistance to ensure that the impaired individual’s own autonomy and preferences are being respected. Neuropsychological assessments, using standardized and validated instruments, can provide some objective data about impairments and abilities which may help inform these complex decisions.
• Individuals may lose the ability to drive safely in the setting of vision, physical and cognitive problems. A driving evaluation, generally performed by occupational therapists, may be helpful. Clinicians need to partner with families to develop subsequent plans. In some states, clinicians can report concerns to authorities such as the Department of Motor Vehicles. In many other states, however, clinicians are not able to report and instead need to ask family members to help enforce recommendations. A social worker or other community resource expert can help identify alternative methods of transportation when needed.

Mild Cognitive Impairment:

• Since individuals with MCI have increased risk of developing dementia, they should undergo regular monitoring. While there are no specific guidelines, clinicians should follow an objective measure every 6 to 12 months or when new symptoms develop.
• Given the overlap between MCI and depression, individuals with MCI benefit from screening and evaluation for depression. If depression is diagnosed, it should be treated. Having both MCI and depression may lead to an even higher risk of MCI progressing to dementia. It is possible, then, that treating the depression can attenuate at least some of that risk.  

Coordination of care

Transitions between hospital units, rehabilitation units, and long-term care facilities should include effective communication and care coordination. Clinicians in receiving units and facilities can then plan for appropriate patient-centered interventions.

Patient & family education

Families may find that the National Institute of Health’s National Institute on Aging-Alzheimer’s Disease Education and Referral Center (ADEAR), and the Alzheimer’s Association and Related Disorders sites can be helpful.²⁷ Local support groups and resources should also be identified for caregivers.

Caregivers should be educated to look for cognitive decline and to recognize small stressors which can lead to medical and functional decline. Family members should apply strategies to allow uninterrupted sleep and optimal activity levels. Exercise should also be encouraged. Families also need education regarding their need for rest and support to avoid caregiver burnout and related stress.

Emerging/unique interventions

Assessment and diagnosis of AD:

The role of neuroimaging in Alzheimer’s Disease diagnosis is a debated topic. MRI is recommended after clinical evaluation. Indication for subsequent amyloid-PET vs. ¹⁸FDG-PET is dependent on clinical context.  Imaging biomarkers in the diagnosis of Alzheimer’s Disease include medial temporal lobe atrophy found on MRI, hippocampal, posterior cingulate, or temporoparietal hypometabolism on ¹⁸FDG-PET, and cortical amyloid-Beta deposits on amyloid-PET studies.¹⁰

Genetic testing: Testing for the presence of AD dominant mutation in presenilin 1, presenilin 2, or amyloid precursor protein, may also help in confirming diagnosis of AD.^10,13

Genetic testing should be obtained in collaboration with appropriate specialists. Genetic counselors can help patients discern their risk prior to testing and can help with test interpretation. Patients and their families need to discuss implications of such testing with each other and with their medical teams prior to being tested and when results come back.¹³

Overlap and interface between delirium and dementia:

• Dementia is the most common risk factor for delirium. Delirium is an independent risk factor for the subsequent development of dementia. They likely share at least some pathological mechanisms.
• It is possible that applying the principles for preventing and treating delirium more broadly and to well older adults could help develop cognitive reserve and prevent precipitous degrees of cognitive decline in people with dementia.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Diagnosis of delirium and dementia can be improved by clinicians becoming more aware of the conditions, educating the public, incorporating cognitive assessment into routine practice, and using available screening instruments.

Cutting Edge/ Emerging and Unique Concepts and Practice

• Prevention of delirium with melatonin/ramelteon:
  • Melatonin and its precursor, L-Tryptophan, have been trialed as preventive agents in patients who are at risk for delirium. It is possible that the delirious state results from a deficiency of tryptophan and a subsequent serotonin deficiency. Plus, lower melatonin levels could lead to sleep-wake cycle problems. Therefore, supplementing with these agents might be helpful. Trials are ongoing.²⁸
  • Ramelteon is a melatonin-receptor agonist that has also been evaluated in the prevention and treatment of delirium. It has been shown to decrease the incidence of delirium in hospitalized patients. However, more studies are required to determine optimal dosage and whether it can prevent the development of delirium in other settings.^29,30
• Complementary, alternative, and integrative medicine interventions for hyperactive delirium/ agitated behaviors:
  • Interventions can include aromatherapy, therapeutic music/dancing, and animal-assisted therapy. Therapeutic touch and tactile stimulation, along with massages of feet, hands, head, and face have also been tried. These interventions should be designed and implemented with the patient’s pre-morbid preferences in mind. Studies regarding efficacy and safety are ongoing.³¹
• Cognitive stimulation in dementia:
  • There is emerging evidence that multifaceted cognitive stimulation can limit cognitive decline. Interventions can include multi-sensory stimulation with a combination of lighting effects, music or sounds, scents, tactile experiences, and balance challenges. Optimal regimens have not yet been developed.²³

Gaps in the Evidence-Based Knowledge

MCI’s relationship to dementia:

• MCI appears to be a precursor to dementia, at least in some people. Standard strategies for monitoring, at some point perhaps treating, individuals with MCI would be helpful.

 Physical activity:

• Exercise has been shown to have benefits on cognition. Additional evidence, and more concrete guidelines for the timing, type, frequency, and intensity of exercise to recommend, are needed.

Cognitive stimulation:

• Cognitive stimulation and activity may be beneficial for individuals with dementia. Standard recommendations for treatment regimens would help guide care planning.

Guidelines for genetic testing for Alzheimer’s Disease: As testing becomes less expensive and more widely available, ethical dilemmas may become more common. For example, an individual may find out that he or she carries a gene that puts him or her at increased risk for AD before symptoms appear. This information could affect decisions made by the individual and family members in other generations who may also have the gene. Guidelines for testing and for addressing positive results could help clinicians effectively navigate these challenging situations.

References

1. De J, Wand APF. Delirium screening: A systematic review of delirium screening tools in hospitalized patients. Gerontologist. 2015;55(6):1079-1099.
2. Bowman EML, Cunningham EL, Page VJ, et al. Phenotypes and subphenotypes of delirium: A review of categorization and suggestions for progression. Crit Care. 2021;25(1): 334. Doi: 10.1186/s13054-021-0372-w.
3. Pink J, O’Brien J, Robinson L, et al. Dementia: Assessment, management and support. Summary of updated NICE guidance. BMJ. 2018;361:k2438. doi:10.1136/bmj.k2438
4. Jongsiriyanyong S, Limpawattana P. Mild cognitive impairment in clinical practice: A review article. Am J Alzheimers Dis Other Demen. 2018;33(8):500-507.
5. Ringman JM. Update on Alzheimer’s and the dementias. Neurol Clin. 2017;35(2):171-174. doi:10.1016/j.ncl.2017.01.009
6. Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386:1672-82. doi:10.1016/S0140-6736(15)00461-4
7. Hshieh TT, Inouye SK, Oh ES. Delirium in the elderly. Psychiatr Clin North Am. 2018;41(1):1-17. doi:10.1016/j.psc.2017.10.001
8. Mattison MLP. Delirium. Ann Intern Med. 2020;173(7):ITC49-ITC64. doi:10.7326/AITC202010060
9. Pun BT, Badenes R, Heras La Calle G, et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A multicentre cohort study. Lancet Respir Med. 2021;9(3):239-250. doi:10.1016/S2213-2600(20)30552-X
10. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577-1590. doi:10.1016/S0140-6736(20)32205-4
11. Cass SP. Alzheimer’s Disease and exercise: A literature review. Curr Sports Med Rep. 2017;  2017;16(1):19-22. doi:10.1249/JSR.0000000000000332
12. Karssemeijer EGA, Aaronson JA, Bossers WJ, et al. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis. Ageing Res Rev. 2017;40:75-83. doi:10.1016/j.arr.2017.09.003
13. Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and management of dementia: Review. JAMA. 2019;322(16):1589-1599. doi:10.1001/jama.2019.4782
14. Lu PH, Lee GJ. The role of neuropsychology in the assessment of the cognitively impaired elderly. Neurol Clin. 2017;35(2):191-206. doi:10.1016/j.ncl.2017.01.002
15. Wei LA, Fearing MA, Sternberg EJ, et al. The Confusion Assessment Method: A systematic review of current usage. J Am Geriatr Soc. 2008;56(5):823-30. doi:10.1111/j.1532-5415.2008.01674.x
16. Grover S, Kate N. Assessment scales for delirium: A review. World J Psychiatry. 2012;2(4):58-70. doi:10.5498/wjp.v2.i4.58
17. Park J, Jeong E, Lee J. The Delirium Observation Screening Scale: A systematic review and meta-analysis of diagnostic test accuracy. Clin Nurs Res. 2021;30(4):464-473. doi:10.1177/1054773820961234
18. Breton A, Casey D, Arnaoutoglou NA. Cognitive tests for the detection of mild cognitive impairment (MCI), the prodromal stage of dementia: Meta-analysis of diagnostic accuracy studies. Int J Geriatr Psychiatry. 2019;34(2):233-242. doi:10.1002/gps.5016
19. Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 09 26 2017;318(12):1161-1174. doi:10.1001/jama.2017.12067.
20. Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for treating delirium in hospitalized adults: A Systematic Review. Ann Intern Med. 2019;171(7):485-495. doi:10.7326/M19-1860
21. Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA Approval of Aducanumab. N Engl J Med. 2021;385(9):769-771. doi:10.1056/NEJMp2110468
22. Walsh S, Merrick R, Milne R, et al. Aducanumab for Alzheimer’s disease? BMJ. 2021;374:n1682. doi:10.1136/bmj.n1682
23. Cafferata RMT, Hicks B, von Bastian CC. Effectiveness of cognitive stimulation for dementia: A systematic review and meta-analysis. Psychol Bull. 2021;147(5):455-476. doi:10.1037/bul0000325
24. De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, et al. Physical exercise in the prevention and treatment of Alzheimer’s disease. J Sport Health Sci. 2020;9(5):394-404. doi:10.1016/j.jshs.2020.01.004
25. Herold F, Törpel A, Schega L, et al. Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements: A systematic review. Eur Rev Aging Phys Act. 2019;16:10. doi:10.1186/s11556-019-0217-2
26. Jennings A, Cunnane SC, Minihane AM. Can nutrition support healthy cognitive ageing and reduce dementia risk? BMJ. 2020;369:m2269. doi:10.1136/bmj.m2269
27. Alzheimer’s Disease & Related Dementias. National institute of Health: National Institute on Aging. Accessed 2/19/2022, 2022. https://www.nia.nih.gov/health/alzheimers
28. Walker CK, Gales MA. Melatonin receptor agonists for delirium prevention. Ann Pharmacother. 2017;51(1):72-78. doi:10.1177/1060028016665863
29. Kim MS, Rhim HC, Park A, et al. Comparative efficacy and acceptability of pharmacological interventions for the treatment and prevention of delirium: A systematic review and network meta-analysis. J Psychiatr Res. 2020;125: 164-176. doi:10.1016/j.jpsychires.2020.03.012
30. Wu YC, Tseng PT, Tu YK, et al. Association of delirium response and safety of pharmacological interventions for the management and prevention of delirium: A network meta-analysis. JAMA Psychiatry. 2019;76(5): 526-535. doi:10.1001/ jamapsychiatry.2018.4365
31. Levy I, Attias S, Ben-Arye E, Bloch B, et al. Complementary medicine for treatment of agitation and delirium in older persons: A systematic review and narrative synthesis. Int J Geriatr Psychiatry. 2017;32(5):492-508. doi:10.1002/gps.4685.

Original Version of the Topic

Deepthi S. Saxena, MD. Delirium and Dementia. 9/20/2013

Previous Revision(s) of the Topic

Diane Schretzman Mortimer, MD. Delirium and Dementia. 8/16/2017

Author Disclosure

Diane Schretzman Mortimer, MD 
Nothing to Disclose

Marcus Babcock, BS
Nothing to Disclose