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Mental Health > NCLEX Cognitive Disorders: Delirium, Dementia, and Amnestic Disorders > Flashcards

NCLEX Cognitive Disorders: Delirium, Dementia, and Amnestic Disorders Flashcards

A patient diagnosed with moderate dementia consistently appears to be distorting the truth resulting in his wife asking, “What should I do when he lies to me about unimportant things?” Upon what rationale should the nurse’s response be based?

a. Changing the topic provides diversion. b. Delusions should be confronted to clarify thinking. c. Ignoring memory deficit avoids catastrophic reactions. d. This isn’t lying but rather a way to fill in the memory gaps.

ANS: D Confabulation is not lying but rather a method for filling in the memory gaps. Ignoring, using confrontation, and changing the topic would not be as useful as gently reorienting.

The nurse is to perform a complete assessment of a patient in her home, using the Mini-Mental State Examination (MMSE) as one component. When the nurse arrives, the patient is seated at the table with her husband, the TV is on, and several grandchildren are visiting. The patient is quiet, but her hands are gripped tightly, and she is staring at the ceiling. The best action for the nurse to take would be which of the following?

a. Ask the husband to make an appointment to bring his wife to the clinic for testing. b. Explain to the husband that accurate data will be sought, and ask him to stay with the grandchildren in another room. c. Do not perform the test during the assessment (because it will not be valid) and rely on observations and reports from the family. d. Explain the importance of the testing process and make an appointment for another day when the environment can be better controlled.

ANS: D Testing the patient in her home under quieter, less distracting circumstances is the best solution. Asking the husband to leave is likely to increase the patient’s anxiety and alter test results. Use of the MMSE is an integral component of the assessment and must not be deleted. Testing in the more familiar, comfortable surroundings of the home will yield more reliable results.

A patient has been admitted with a diagnosis of hypoactive delirium. Which nursing intervention is supported by this diagnosis?

a. Encouraging fluids to minimize constipation b. Frequently assessing both visual and auditory hallucinations c. Scheduling frequent changing of position to prevent skin breakdown d. Dimming the lights to help control eye discomfort resulting from cataracts

ANS: C Because of inactivity, hypoactive delirium patients are more likely to develop further complications, including decubiti that could be minimized by frequent repositioning. The remaining options identify interventions that are not generally a result of this diagnosis

Which of the following should the nurse use as a basis for explaining the etiology of Alzheimer’s disease to the family of a patient with this disease?

a. It is a secondary dementia indicated by loss of recent memory and disorientation to time and place. b. It is a primary dementia that is incurable, irreversible, and fatal. It is caused by the presence of a beta-amyloid protein in the neurons resulting in senile plaques. c. It is a secondary dementia that is treatable with analysis of the diet and removal of toxic substances from the diet and environment. d. It is a primary dementia characterized by stepwise decreases in cognitive abilities. It is irreversible but treatable with antihypertensive medications.

ANS: B This option provides accurate information about Alzheimer’s disease. Alzheimer’s disease is not a secondary dementia nor is it treated with antihypertensive medications.

Which outcome is realistic for a patient with stage 1 Alzheimer’s disease?

a. Caregiver will assume role of decision maker for patient to reduce stress. b. The patient will maintain the highest possible functional level to preserve autonomy. c. Arrangements will be made for appropriate long-term placement to minimize risk of injury. d. The patient will retain full physical functioning through cognitive and occupational therapies.

ANS: B This outcome addresses health maintenance (i.e., maintaining an optimal functional level as determined by present capacity). Although long-term placement may be an option, it is not necessarily appropriate during this stage. Patients in stage 1 are often able to make simple decisions. Continuing to make decisions gives the patient a sense of control. Although a patient in stage 1 does not appear markedly deteriorated, some diminution of function may be present

The home care nurse is visiting a patient who was discharged to home after a procedure at an ambulatory surgical center. The patient lives alone in a senior retirement community. The nurse’s assessment documents mild dysphasia. The patient repeatedly asks, “Why is there a bandage on my arm?” and is not able to state the appropriate day and year. Appropriate planning for the patient should include:

a. Assessing diet and meal preparation, assessing environment for safety problems, referral to a dementia program b. Attending English class to improve speech, transferring finances to a conservator, employing an aide to help with medications c. Arranging Meals on Wheels, attending speech therapy, relocation to a skilled nursing facility if no improvement in 1 month d. Arranging an appointment at a geriatric assessment program, OT referral for swallowing therapy, teaching to manage public transportation

ANS: A Further assessment is appropriate before making changes in the living environment. Enrolling in a dementia program will provide stimulation and help the patient maintain intellectual skills. English classes will not improve speech. The other plans might have relevance, however. The remaining sets of options are either irrelevant or beyond the patient’s abilities.

A patient diagnosed with Alzheimer’s disease has a catastrophic reaction during an activity involving simultaneous playing of music and working on a craft project. The patient starts shouting “no, no, no” and rushes out of the room. The nurse should:

a. Discontinue the activity program since it upsets the patients. b. Follow the patient, reassure her, and redirect her to a quieter activity. c. Isolate the patient until she is calm, and then direct her back to the activity. d. Give the patient prn antianxiety medication and restrict her activity participation.

ANS: B These actions will restore safety and self-esteem. Isolation will decrease self-esteem and may increase confusion. It is only one patient that is distressed, not the entire group. Behavioral interventions should be attempted prior to administering medication.

Which behaviors would indicate that a therapeutic activity program for a patient with Alzheimer’s disease had been successful?

a. Accurate recent memory, positive emotional response, and increased verbal expression b. Increased attention span, verbal expression of remote memory, and positive emotional response c. Positive use of perseveration, reduction in use of habitual skills, and improved abstract reasoning d. Positive emotional response, ability to remember multiple steps, and accurate recent memory

ANS: B These are all observations that would indicate that a therapeutic activity program has kept the patient functioning at the highest level of which he is capable. The behaviors described in the other options are not realistic expectations for this patient.

A patient has been diagnosed with dementia secondary to cerebral disease. The family members note the patient “has not been as sharp as he once was” and that he has developed urinary incontinence and a gait disturbance. Which pathophysiology can cause such symptoms?

a. Normal pressure hydrocephalus b. Vitamin B12 deficiency c. Hepatic disease d. Tuberculosis

ANS: A Normal pressure hydrocephalus is a disorder characterized by dementia, gait disorder, and urinary incontinence. Dilation of ventricles in the absence of increased CSF is a prominent manifestation. Early urinary incontinence is not seen in the disorders listed in the other options

When asked about the prognosis for a patient diagnosed with a dementia secondary to normal pressure hydrocephalus the nurse replies:

a. “Unfortunately the prognosis is for a downhill course ending in death.” b. “There will be good days and bad days for the rest of the patient’s life.” c. “The symptoms generally remit after a shunt is inserted to drain fluid.” d. “We’ll try our very best, but only time will tell how successful we are.”

ANS: C By relieving the cause, the symptoms of secondary dementias are largely reversible. The statements reflected in the other options do not reflect this fact.

Which statement by an adult child concerning the behaviors of their parent supports the diagnosis of Alzheimer’s disease?

a. “Mom forgot to pay her utility bills last month.” b. “Mom isn’t as interested in keeping a neat house as she was.” c. “Mom doesn’t seem interested in going out with friends anymore.” d. “Mom refuses to stop driving even though her reaction time is very slow.”

ANS: A Increased forgetfulness, particularly that involving former routine activities (such as bill paying), is symptomatic of Alzheimer’s disease. The other options do not indicate cognitive deficit.

The daughter of an older patient with dementia tearfully tells the nurse that she doesn’t know what’s wrong with her mother, who has begun accusing the family of holding her prisoner. Which nursing diagnosis would be appropriate for this patient?

a. Powerlessness b. Defensive coping c. Ineffective coping d. Disturbed thought processes

ANS: D Paranoid thinking is common in patients with dementia. Inability to correctly interpret environmental clues and to think logically leads to delusional thinking as the patient tries to make sense of a confusing world. The remaining options are not supported by the data in the scenario.

The daughter of an elderly patient with dementia tearfully tells the nurse that she doesn’t know what’s wrong with her mother, who has begun accusing the family of stealing her money. The nurse assesses the patient’s stage of Alzheimer’s disease as stage:

a. 1 b. 2 c. 3 d. 4

ANS: B In stage 2, memory and cognitive deficits are worsening. The patient is less able to make sense of a confusing world and makes faulty interpretations resulting in paranoid delusional thinking. The patient in stage 1 does not usually have delusions. The patient in stage 3 often is unable to communicate meaningfully. There is no stage 4 of Alzheimer’s disease

An elderly patient was well until 12 hours ago, when she reported to her family that in the middle of the night she awakened to see a man standing at the foot of her bed. There is no evidence that this situation ever happened. This series of events supports which possible diagnosis?

a. Delirium b. Anxiety c. Paranoia d. Dementia

ANS: A Delirium is a disturbance of consciousness and cognition that develops over a short period. It is secondary to a medical condition. The scenario does not fit the disorders mentioned in the remaining options.

A patient diagnosed with delirium has become agitated and fearful. Which nursing intervention should the nurse implement to help prevent a catastrophic response?

a. Interact with the patient on an adult-to-child level. b. Place the patient in a safe, nonstimulating environment. c. Ask the patient to explain what is causing the agitation and fear. d. Be prepared to apply physical restraints to minimize the patient’s risk for injury.

ANS: B The safety of a patient with delirium is of primary importance. Symptoms of delirium fluctuate and may worsen, especially at night. The greater the patient’s confusion and disorientation, the greater the possibility for self-harm. The patient should be treated as an adult; to do otherwise is demeaning. Asking for an explanation is inappropriate, because delirious patients cannot formulate rational answers. Patients are never restrained unless all other less restrictive measures have failed.

A patient has been diagnosed with Alzheimer’s disease, stage 1. The nurse would expect to help the family plan measures to assist the patient with:

a. Perseveration b. Recent memory loss c. Catastrophic reactions d. Progressive gait disturbances

Recent memory loss is the only symptom listed in the options that would be expected in stage 1 Alzheimer’s disease.

An elderly patient with dementia has a nursing diagnosis of self-care deficit: bathing, hygiene. She lives alone and the nursing assessment proves reason to believe she has forgotten how to perform hygiene and bathing activities. Which intervention is most appropriate for this patient?

a. Bathe daily with reminders. b. Bathe twice weekly with assistance. c. Patient will be provided with in-home nursing care. d. Patient will be transferred to an assisted living facility.

ANS: B Bathing twice weekly would be a realistic goal. Assistance should be provided, both to prevent falls and to regulate shower temperature. The elderly are advised not to bathe daily because it is too drying to their skin. The remaining options are not supported by the information given in the scenario.

Which situation would be most likely to serve as a trigger to a catastrophic reaction in a patient with stage 2 Alzheimer’s disease?

a. Participating in singing “Happy Birthday” to another patient at dinner b. Being scolded by an aide for spilling a glass of milk c. Listening to Big Band music from the 1940s d. Eating cupcakes in the activities room

ANS: B Catastrophic reactions are overexaggerated negative emotional responses initiated as a result of a perceived failure at a task or change in the environment. Being scolded by the aide presents a situation that would clearly be frustrating to the patient.

Which theory of etiology of Alzheimer’s disease, suggested by current research, might the nurse use to help a family understand that this disorder is not of psychosocial origin? Alzheimer’s disease is associated with:

a. Abnormal serotonin reuptake b. Prion infection of gray matter c. ß-Amyloid protein deposits in the brain d. Excessive acetylcholine in the frontal cortex

ANS: C The prevailing theories of etiology of Alzheimer’s disease include the following: angiopathy and blood-brain barrier incompetence; neurotransmitter and receptor deficiencies of acetylcholine; abnormal proteins, specifically ß-amyloid and their products; and genetic defects. Neither serotonin nor prions are implicated as problems in Alzheimer’s disease.

The nurse is administering donepezil (Aricept) to a patient with stage 1 Alzheimer’s disease. Based on this drug’s mechanism of action, the nurse will seek evidence of improvement in the patient’s:

a. Social behaviors b. Existing delusions c. Ability to tolerate stress d. Ability to remember recent events

ANS: D Donepezil is a cholinesterase inhibitor that increases the concentration of acetylcholine. Acetylcholine is needed for intact memory and for learning. This medication is not prescribed for the conditions identified in the remaining options.

A patient with dementia is unable to name ordinary objects. Instead, he describes the function of each item (e.g., “the thing you cut meat with”). The nurse assesses this as:

a. Apraxia b. Agnosia c. Aphasia d. Amnesia

ANS: B Agnosia is the failure to identify objects despite intact sensory function. Apraxia is the inability to carry out purposeful, complex movements and use objects properly. Aphasia refers to inability to speak (expressive) or inability to comprehend what is said or written (receptive). Amnesia is inability to remember a significant block of information.

Which intervention has highest priority for a patient with stage 3 Alzheimer’s disease?

a. Cutting the patient’s food into bite size pieces b. Providing fluids to the patient every hour while awake c. Demonstrating to the patient how to put toothpaste on the brush d. Assisting the patient in signing a birthday care for a granddaughter

ANS: B The severe dementia characteristics of stage 3 renders the patient incapable of independently meeting hydration and nutrition needs. These needs are basic to life, so they are of highest priority. The remaining options are not applicable for such an impaired patient.

A patient was admitted to a dementia unit after persistently wandering away from home. Which intervention will best address this patient’s risk for injury?

a. Place the patient in a geriatric chair with a tray across the lap. b. Provide one-to-one supervision when the patient is ambulatory. c. Reinforce verbal explanation to the patient concerning the dangers of wandering. d. Activate alarm system that will alert staff to the patient’s attempt to open the door.

ANS: D Electronic alarms allow patients freedom of movement although still preventing them from wandering off the unit. One-to-one supervision is not necessary in an environment designed as a dementia unit. The geriatric chair would be an unacceptable form of restraint for this patient. The patient would not be capable of processing the verbal explanation.

A patient with moderate dementia does not remember her son’s name. The son repeatedly questions the mother asking, “Do you know my name?” The mother invariably becomes agitated. The nurse can most effectively intervene by explaining to the son:

a. “Your mother is angry with you and is punishing you by ‘forgetting’ who you are. Be patient and she’ll get over it.” b. “Your mother’s dementia is preventing her from retaining information even for short periods of time. She senses your distress and becomes agitated.” c. “You will need to reorient your mother often during your visits with her. With reinforcement, she may be able to begin to recall who you are.” d. “Because you both become so distressed, it might be better if you come to see your mother less frequently and stay for only shorter periods of time.”

ANS: B When a patient with dementia is presented with a demand that exceeds their capacity to function, the demand creates a high level of stress. Showing anxiety and disapproval adds even greater stress. The son should be counseled to make every attempt to demonstrate positive responses to his mother. The other options are not effective interventions.

The wife of a patient with moderate to severe dementia tells the nurse, “I’m exhausted. He wanders at night instead of sleeping, so I get no rest. I’m afraid to leave him during the day, so I have to take him with me wherever I go.” The nurse recognizes the need to provide teaching for this caregiver. An appropriate outcome for this teaching would include:

a. Experiences less stress indicated by improved sleep patterns b. Feels comfortable leaving the patient in the care of others occasionally c. No longer experiences resentment concerning the need to care for the patient d. Feels at peace with the decision to admit the patient to an appropriate care facility

ANS: A Stress reduction allowing for better rest is an appropriate outcome. The other options are not necessarily appropriate nor will they result in improvement for the caregiver.

A teenager is admitted to the ED after being alternately hyperalert and difficult to arouse. The symptoms started within the last few hours, during which time he became disoriented, confused, and delusional. These symptoms support the diagnosis of:

a. Amnesia b. Delirium c. Dementia d. Depression

The symptoms are indicative of delirium. The other options are not supported by the scenario

Which interventions provided by the caregiver will help ensure effective care for the patient diagnosed with dementia? (Select all that apply)

a. Taking the patient’s blood pressure regularly b. Being alert to ways the patient might be hurt c. Keeping the patient on a predictable schedule d. Assuming responsibility for meeting the patient’s needs e. Providing the patient with nonstimulating, private time

ANS: B, C, E These interventions take responsibility for areas in which the patient is incapable of providing self-care and addressing the special needs this patient has. Taking the blood pressure is not necessary unless there is a medical condition that requires doing so. Although the patient’s ability to provide self-care will deteriorate, independence should be encouraged as appropriate.

For which medication will the nurse prepare material for the family of a patient diagnosed with mild to moderate Alzheimer’s disease? (Select all that apply.)

a. Tacrine (Cognex) b. Donepezil (Aricept) c. Haloperidol (Haldol) d. Rivastigmine (Exelon) e. Galantamine (Razadyne)

The only drug that is not generally prescribed for Alzheimer’s disease is Haldol.

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According to the ATI video case study, Cognition: Delirium and Dementia, which of the following is the best first action for the nurse to take when caring for a client with delirium?

Identify the underlying cause

Tell the client that hallucinations are not real

Speak slowly and clearly

Request the assistance of physical therapy

Identify the underlying cause. This is correct because delirium is a reversible condition that is often caused by an underlying medical problem, such as infection, medication, or dehydration.

Identifying and treating the cause can help resolve the delirium and prevent further complications.

Tell the client that hallucinations are not real. This is incorrect because it can increase the client's anxiety and confusion. The nurse should acknowledge the client's feelings and perceptions, but not reinforce or argue with them.

Speak slowly and clearly. This is incorrect because it is not the best first action. While speaking slowly and clearly can help communicate with the client, it does not address the root cause of the delirium.

Request the assistance of physical therapy. This is incorrect because it is not relevant to the question. Physical therapy may be helpful for some clients with delirium, but it is not a priority intervention.

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Related Questions

A client has a history of atrial fibrillation. Which of the following is the nurse likely to see on the clients medication history to prevent stroke?

Correct answer is b.

No explanation

Match the characteristics with the type of stroke. Each characteristic is only used one time. Hypertension primary Cause Symptoms progress over time Rapid progression of symptoms Most common type Symptoms resolve Associated with high risk of stroke Atrial fibrillation primary cause Type of stroke a.Transient Ischemic Attack b.Hemorrhagic Stroke c.Ischemic Stroke

Correct answer is hypertension primary cause b.,hemorrhagic stroke symptoms progress over time b,.hemorrhagic stroke rapid progression of symptoms, c.ischemic stroke most common type ,c.ischemic stroke symptoms resolve ,a.transient ischemic attack associated with high risk of stroke ,a.transient ischemic attack atrial fibrillation primary cause, c.ischemic stroke, a client reports visual disturbances followed by debilitating pain, nausea, and light sensitivity. when providing education for this client, what can the nurse include in teaching select all that apply (select all that apply.), a nurse is assessing a client who has a concussion from a sports injury. which of the following manifestations should the nurse expect, a nurse is receiving a transfer report for a client who has a head injury. the client has a glasgow coma scale (gcs) score of 3 for eye opening, 5 for best verbal response, and 5 for best motor response. which of the following is an appropriate conclusion based on this data, a nurse is providing teaching to a client who has a new diagnosis of parkinson's disease. on which of the following medications should the nurse prepare to instruct the client, a nurse at a community health clinic is caring for a client who reports a headache and stiff neck. which of the following actions should the nurse take first, when providing education to a student nurse about ways to avoid increased intracranial pressure, which of the following will the nurse include in the instructions(select all that apply.), an 84year old client is brought to the emergency department with reports that his mental status has slowly been declining. he fell 2 weeks ago but did not seek medical attention. based on this information, what does the nurse suspect the client's diagnosis will be, according to the ati video case study, cognition: delirium and dementia, when caring for the client with alzheimer's disease, which of the following are appropriate items to include in the client's room.

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Differences Between Delirium and Dementia

Delirium and dementia are conditions that can be confusing, both to experience and to distinguish. Both can cause memory loss, poor judgment , a decreased ability to communicate , and impaired functioning. While the question of delirium vs dementia may seem difficult to answer, there are many differences between the two, including the following:

Dementia: Dementia typically begins slowly and is gradually noticed over time. If the person who's being evaluated is unknown to you, getting a report of their usual functioning is key.

Delirium: Delirium is usually a sudden change in a condition. One day, your loved one is doing fine, and the next, she may be very confused and unable to get dressed . Delirium is also known as acute confusional state , with the key being that it is acute, or sudden.

Dementia: The cause of dementia is typically a disease such as Alzheimer's , vascular dementia , lewy body dementia , frontotemporal dementia or a related disorder.

Delirium: Delirium is usually triggered by a specific illness, such as a urinary tract infection , pneumonia , dehydration, illicit drug use, or withdrawal from drugs or alcohol. Medications that interact with each other can also cause delirium, so make sure your physician knows all of the medications, supplements, and vitamins you're taking, even if they're natural substances.

Dementia: Dementia is generally a chronic, progressive disease that is incurable. (There are some reversible causes of dementia symptoms such as vitamin B12 deficiency , normal pressure hydrocephalus , and thyroid dysfunction).

Delirium: Delirium can last for a couple of days to even a couple of months. Delirium is almost always temporary if the cause is identified and treated.

Communication Abilities

Dementia: People with dementia may have difficulty finding the right words , and the ability to express themselves gradually deteriorates as the disease progresses.  

Delirium: Delirium may significantly and uncharacteristically impair someone's ability to speak coherently or appropriately.  

Attention Span and Memory

Dementia: A person's level of alertness is typically not affected until the late stages of Alzheimer's, whereas memory is significantly affected throughout the disease.  

Delirium: In delirium, the opposite is true. Memory functioning is usually less affected in delirium but the ability to focus and maintain attention to something or someone is very poor.  

Activity Level

Dementia: Dementia tends to not affect a person's activity level until the later stages.

Delirium: People with delirium are often either overly active (hyper and restless) or under-active (lethargic and less responsive) compared to usual functioning.

Dementia: There are currently a handful of  medications approved by the Food and Drug Administration (FDA) to treat Alzheimer's disease, the most common type of dementia. Those medications don't cure dementia but sometimes can slow the progression of the symptoms, including memory loss, poor judgment, behavioral changes and more.

Aduhelm Discontinued

In June 2021, the Food and Drug Administration (FDA) approved Aduhelm (aducanumab) for treating Alzheimer's disease. It was the first drug approved for this disease since 2003 and targets amyloid-beta. However, studies showed little or no benefit in slowing cognitive decline.

In January 2024, Biogen, the drug's manufacturer, announced it would discontinue sales and clinical trials for the drug by the end of November that year.

Delirium: Delirium requires immediate treatment by a physician. Since it's usually caused by a physical illness or infection, medications such as antibiotics often resolve the delirium.

Delirium in People With Dementia

Distinguishing between delirium or dementia is important; however, a more difficult task may be identifying delirium in someone who already has dementia. According to a study by Fick and Flanagan, approximately 22% of older adults in the community with dementia develop delirium. However, that rate skyrockets to 89% for those who have dementia and are hospitalized.  

Knowing how to identify delirium in someone who is already confused is critical for appropriate treatment and a faster recovery. Delirium superimposed on someone with dementia also is connected with a more than double mortality risk compared to those with delirium or dementia alone.  

Delirium Signs to Look For

• Increased agitation
• Unusually resistive to care
• Catastrophic reactions
• Decreased communication
• Inattention
• Fluctuating alertness

A Word From Verywell

Understanding the difference between delirium and dementia can be helpful in identifying if your loved one needs to see the doctor immediately, or if he should be evaluated at an appointment that's scheduled within a few weeks. Be sure to report any signs of delirium, especially a sudden change in functioning or health, to the physician for evaluation and prompt treatment.  

Duong S, Patel T, Chang F. Dementia: What pharmacists need to know .  Can Pharm J (Ott) . 2017;150(2):118–129. doi:10.1177/1715163517690745

The Mayo Clinic. Delirium .

Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment .  Clin Geriatr Med . 2014;30(3):421–442. doi:10.1016/j.cger.2014.04.001

Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people .  Lancet . 2014;383(9920):911–922. doi:10.1016/S0140-6736(13)60688-1

Banovic S, Zunic LJ, Sinanovic O. Communication Difficulties as a Result of Dementia .  Mater Sociomed . 2018;30(3):221–224. doi:10.5455/msm.2018.30.221-224

Green S, Reivonen S, Rutter LM, et al. Investigating speech and language impairments in delirium: A preliminary case-control study .  PLoS One . 2018;13(11):e0207527. doi:10.1371/journal.pone.0207527

Gold CA, Budson AE. Memory loss in Alzheimer's disease: implications for development of therapeutics .  Expert Rev Neurother . 2008;8(12):1879–1891. doi:10.1586/14737175.8.12.1879

O'Regan NA, Ryan DJ, Boland E, et al. Attention! A good bedside test for delirium? .  J Neurol Neurosurg Psychiatry . 2014;85(10):1122–1131. doi:10.1136/jnnp-2013-307053

FDA-approved treatments for Alzheimer’s . Alzheimer's Association [internet].

Grover S, Avasthi A. Clinical Practice Guidelines for Management of Delirium in Elderly .  Indian J Psychiatry . 2018;60(Suppl 3):S329–S340. doi:10.4103/0019-5545.224473

Flanagan NM, Fick DM. Delirium superimposed on dementia. Assessment and intervention .  J Gerontol Nurs . 2010;36(11):19–23.

Morandi A, Davis D, Bellelli G, et al. The Diagnosis of Delirium Superimposed on Dementia: An Emerging Challenge .  J Am Med Dir Assoc . 2017;18(1):12–18. doi:10.1016/j.jamda.2016.07.014

• Flanagan NM, Fick DM. Delirium Superimposed on Dementia: Assessment and Intervention.  Journal of Gerontological Nursing . 2010;36(11):19-23.
• Journal of Gerontology: Medical Sciences. 2007, Vol. 62A, No. 11, 1306–1309. Delirium Superimposed on Dementia Predicts 12-Month Survival in Elderly Patients Discharged From a Postacute Rehabilitation Facility.
• Lippmann S, Perugula ML. Delirium or dementia? 2016;13(9-10). ​ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141598/ . 

By Esther Heerema, MSW Esther Heerema, MSW, shares practical tips gained from working with hundreds of people whose lives are touched by Alzheimer's disease and other kinds of dementia.

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The inter-relationship between delirium and dementia: the importance of delirium prevention

Tamara g. fong.

1 Aging Brain Center, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA USA

2 Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA USA

Sharon K. Inouye

3 Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA USA

Delirium and dementia are two frequent causes of cognitive impairment among older adults and have a distinct, complex and interconnected relationship. Delirium is an acute confusional state characterized by inattention, cognitive dysfunction and an altered level of consciousness, whereas dementia is an insidious, chronic and progressive loss of a previously acquired cognitive ability. People with dementia have a higher risk of developing delirium than the general population, and the occurrence of delirium is an independent risk factor for subsequent development of dementia. Furthermore, delirium in individuals with dementia can accelerate the trajectory of the underlying cognitive decline. Delirium prevention strategies can reduce the incidence of delirium and associated adverse outcomes, including falls and functional decline. Therefore, delirium might represent a modifiable risk factor for dementia, and interventions that prevent or minimize delirium might also reduce or prevent long-term cognitive impairment. Additionally, understanding the pathophysiology of delirium and the connection between delirium and dementia might ultimately lead to additional treatments for both conditions. In this Review, we explore mechanisms that might be common to both delirium and dementia by reviewing evidence on shared biomarkers, and we discuss the importance of delirium recognition and prevention in people with dementia.

In this Review, Fong and Inouye explore mechanisms that might be common to both delirium and dementia. They present delirium as a possible modifiable risk factor for dementia and discuss the importance of delirium prevention strategies in reducing this risk.

• Delirium and dementia are frequent causes of cognitive impairment among older adults and have a distinct, complex and interconnected relationship.
• Delirium prevention strategies have been shown to reduce not only the incidence of delirium but also the incidence of adverse outcomes associated with delirium such as falls and functional decline.
• Adverse outcomes associated with delirium, such as the onset of dementia symptoms in individuals with preclinical dementia, and/or the acceleration of cognitive decline in individuals with dementia might also be delayed by the implementation of delirium prevention strategies.
• Evidence regarding the association of systemic inflammatory and neuroinflammatory biomarkers with delirium is variable, possibly as a result of co-occurring dementia pathology or disruption of the blood–brain barrier.
• Alzheimer disease pathology, even prior to the onset of symptoms, might have an effect on delirium risk, with potential mechanisms including neuroinflammation and gene–protein interactions with the APOE ε4 allele.
• Novel strategies, including proteomics, multi-omics, neuroimaging, transcranial magnetic stimulation and EEG, are beginning to reveal how changes in cerebral blood flow, spectral power and connectivity can be associated with delirium; further work is needed to expand these findings to patients with delirium superimposed upon dementia.

Introduction

Cognitive impairment is frequent among older adults, with delirium and dementia being two of the most common causes. Delirium refers to a disturbance in attention and awareness that is acute in onset and represents a change from baseline cognitive function 1 . At least one additional cognitive disturbance is required for diagnosis, for example, disturbance of memory, orientation, language, visuospatial ability or perception; fluctuations in mental status throughout the day are also present. For a diagnosis of delirium, these disturbances cannot be better explained by another neurocognitive disorder and there must be evidence that the disturbances are a consequence of a medical condition, substance intoxication or withdrawal, a toxin, or multiple aetiologies. Often precipitated by illness or hospitalization in older adults, delirium is associated with poor short-term and long-term outcomes, including prolonged length of hospital stay, institutionalization, functional and cognitive decline, and death 2 . In the United States, more than 2.6 million adults aged 65 years and older develop delirium each year 3 . The health-care costs associated with delirium are estimated at more than US$ 164 billion per year in the United States 4 and over US$ 182 billion per year in 18 European countries combined 5 , 6 .

Dementia refers to a progressive loss of a previously acquired cognitive skill and can be used as an umbrella term for many types of progressive cognitive decline. Alzheimer disease (AD), which presents as a progressive loss of cognitive ability, often memory, but including language, orientation and the ability to perform daily tasks, is the most common form of dementia 7 . An estimated 50 million people have dementia worldwide and this figure is projected to triple by 2050 (ref. 8 ). Associated costs are also expected to rise from the estimated US$ 1 trillion globally in 2018 to US$ 2 trillion by 2030 (ref. 8 ).

Despite the global impact of delirium and dementia, treatment options for these common conditions are limited. For example, although symptomatic treatments for dementia are available, the benefit of these strategies has been modest for most patients 9 . Much effort has been devoted to finding disease-modifying drugs for dementia, but until 2021 no new dementia treatments had been approved by the FDA since 2003 (ref. 10 ). For delirium, pharmacological treatment strategies, including haloperidol, second-generation antipsychotics 11 , melatonin 12 or cholinesterase inhibitors 13 , have been tested but were not found to be effective either for prevention or treatment. Current practice guidelines reflect the consensus that drugs should not be used as a treatment for delirium 2 , with the exception of antipsychotic medications when behaviours pose a safety risk to patients, staff or both, or when there is a risk of interrupting essential medical care 3 , 14 .

Delirium and dementia have a complex inter-relationship. Individuals who develop delirium have a higher risk of developing dementia than the general population 15 , 16 ; however, whether delirium simply serves to unmask unrecognized dementia or an overlap in the pathophysiology of delirium and dementia initiates or accelerates neurodegeneration, remains unclear. Cognitive impairment and dementia are independent risk factors for developing delirium 15 and, moreover, delirium has been associated with an acceleration in long-term cognitive decline both in individuals with 17 – 21 and without dementia 22 , 23 . Evidence indicates that people with dementia who develop delirium have longer lengths of hospital stays, greater cognitive and functional decline, and a higher risk of institutionalization and mortality than people with dementia who are hospitalized and do not develop delirium 24 . Delirium prevention strategies have been consistently demonstrated to be successful in reducing the incidence of delirium and adverse outcomes, such as falls, cognitive and functional decline 25 , 26 , length of hospital stay 27 , 28 , use of sitters 29 , institutionalization 29 , readmissions 30 , and health-care costs (hospital and 1-year), in mixed samples, including persons both with and without dementia 31 – 35 . These observations suggest that delirium prevention might also be useful in ameliorating the effect of delirium on the cognitive trajectory in dementia.

Understanding the inter-relationship between delirium and dementia might ultimately lead to more effective treatments for both conditions. Work performed over the last 5 years has led to important advances in delirium research, including harmonization of diagnostic and measurement tools, heightened awareness of delirium, widespread delirium screening, and implementation of clinical guidelines and pathways to optimize care. The development of ultrasensitive assays for the measurement of plasma biomarkers has furthered research into and understanding of delirium pathophysiology. In keeping with the importance of delirium, a number of comprehensive systematic reviews have been published in the past 3 years, most notably on delirium 2 , delirium prevention in dementia 36 , delirium in hospitalized older adults 24 and delirium biomarkers 37 . In this Review, we focus on clinical and epidemiological aspects of delirium in people with dementia, examine the evidence for shared mechanisms between delirium and dementia, and discuss delirium prevention in persons with dementia.

Delirium in people with dementia

Clinical features.

Dementia and delirium are distinct but inter-related conditions and, at times, are mistaken for each other. The occurrence of delirium in a person with dementia, known as delirium superimposed on dementia (DSD) 38 , is often unrecognized, making clinical diagnosis challenging. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) makes a point of classifying delirium as being distinct from a “pre-existing established, or evolving neurocognitive disorder”, and states that “dementia should not be diagnosed in the face of delirium” 1 . A key feature in distinguishing delirium from dementia is the presence of an acute change in mentation from baseline or resolution of symptoms with treatment of precipitating factors (for example, infection, dehydration, drugs). A person with AD will experience a decline in memory and cognition that is typically insidious and progressive over months to years and will have preserved consciousness. By contrast, the symptoms suggestive of delirium would include information from a proxy of an acute change in mental status over hours to days characterized by confusion and inattention, fluctuating symptoms, and altered consciousness. Table  1 is a simplified comparison of the symptoms of delirium with the most common symptoms of key types of dementia; however, the concept of DSD, discussed in more detail below, is still applicable broadly to all forms of dementia.

Features of delirium and dementia

Epidemiology

In 2017, a large ( n  = 1,409) prospective cohort study of hospitalized adults over the age of 60 found the prevalence rate of DSD to be 31% 39 , whereas a 2021 meta-analysis of 81 studies, including 81,536 people with dementia, reported a pooled DSD prevalence of 48.9% in patients with dementia during hospitalization 24 . Nevertheless, the reported prevalence rates of DSD across studies are highly variable owing to differences in diagnostic approaches used, the overlap of symptoms between delirium and dementia, and differences in study populations (for example, higher rates are observed in populations with older ages and in medical versus surgical populations), prospective versus retrospective approaches to diagnosis and other aspects of study methodology 24 , 39 . By extrapolating from many studies, we previously estimated that delirium will develop in 1 in 2 to 1 in 5 patients with dementia who are hospitalized, which translates to a 3–4 times higher risk of delirium than patients without dementia 40 . Regardless of the variation in prevalence estimates, DSD is common and, as the global population ages 41 , the diagnosis and treatment of this condition are likely to emerge as serious challenges. Indeed, in one study, patients with DSD had a 2.6-fold higher risk of in-hospital death than patients without cognitive impairment (neither delirium nor dementia), whereas dementia alone was not associated with a statistically significant increased risk of in-hospital death (1.5-fold higher than patients without cognitive impairment; non-significant) 42 .

Despite being a common syndrome, DSD often goes undetected or is misattributed to underlying dementia, which contributes, at least in part, to the wide range of prevalence rates reported across studies. Furthermore, these numbers might substantially underestimate the true prevalence, particularly when people have a form of dementia for which the symptom profile overlaps with that of delirium, for example, diffuse Lewy body disease, in which symptom fluctuations are common 38 . Furthermore, the formalized criteria for the diagnosis of delirium, for example, those given in the DSM-5 (ref. 1 ), do not include specific cognitive tests, criteria, or guidance for diagnosis of delirium in the setting of dementia or pre-existing cognitive impairment, which adds to the difficulty of diagnosing DSD.

The results of a survey among clinicians who encounter DSD showed that, despite individual clinician confidence in recognizing DSD, global consensus in assessment and diagnosis is lacking 43 . Baseline cognitive status is often unknown in older adults upon hospital admission. If no established diagnosis of dementia is available in the medical record or from a family member, a screening tool, such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) 44 , can be completed by a proxy who has known the patient for the past 10 years. Alternatively, the Eight-item Interview to Differentiate Aging and Dementia (AD8) can be used with a proxy that knows the patient well and can rate change over the past several years 45 . Although many delirium screening tools are available 2 , relatively few have been assessed in formal studies that used large cohorts and controlled for dementia subtype or severity 46 . Standard diagnostic criteria for delirium, such as those in the DSM-5 or the International Classification of Diseases, Tenth Revision (ICD-10), are limited in their application to DSD as neither provides specific recommendations for tests to assess attention, cognition and level of consciousness 38 . Furthermore, the variability and progressive decline in cognitive impairment among people with dementia present a unique challenge in selecting an appropriate test to measure cognitive impairment; substantial overlap of symptoms in delirium and dementia can also occur (as mentioned above and described in Table  1 ).

One instrument explicitly modified to identify delirium in the presence of dementia is the 4-DSD 47 , which is a 4-item scale based on the 4-AT (Arousal, Attention, Abbreviated Mental Test-4, Acute change) 48 . The 4-DSD has a range of 0–12; higher scores suggest the presence of delirium. However, the psychometric properties of the 4-DSD vary depending on the severity of the cognitive impairment 47 , and high scores on some items in the 4-DSD, such as unawareness, presence of sleep–wake disorder and inattention, might be a result of the underlying dementia process and not the delirium. Furthermore, symptoms such as agitation, aggression or psychomotor retardation, which can occur in both delirium and dementia, are not used in the assessment. Other instruments include the Confusion Assessment Method (CAM) 49 and the 3D-CAM 50 , a brief diagnostic tool derived from the CAM algorithm. These two tools have had relatively limited testing in people with dementia 50 but are flexible in the type of assessment used to score the items; for example, attention can be assessed using the months of the year backwards test or simple counting, depending on the severity of cognitive impairment. More recent strategies use brief assessments, which are better tolerated by persons with dementia, to quickly exclude delirium. These strategies include the ultra-brief CAM (UB-CAM) 51 or the months of the year backwards test 52 , where delirium is associated with the inability to engage and complete the task. For all of these tests, the features most crucial to identifying DSD are establishing baseline status and recognizing the presence of an acute change in symptoms or behaviours.

Delirium can also vary in severity. Instruments measuring delirium severity, such as the Memorial Delirium Assessment Scale 53 , the Delirium Rating Scale–revised-98 (ref. 54 ) or the CAM-S long form 55 , also face the same challenges as delirium screening tools as symptoms of dementia can affect these severity measurements. Evidence indicates that the CAM-S short form 55 is less subject to these biases than the CAM-S version, and might be a better measure of delirium severity in this setting. Ultimately, future research is needed to develop reliable screening tests and reference standards for diagnosing DSD 38 and measuring delirium severity in persons with dementia.

Delirium as a modifiable risk factor for dementia

Evidence indicates that delirium is associated with the acceleration of cognitive decline in people with dementia 20 , 21 . Results from the Delirium and Cognitive Impact in Dementia (DECIDE) study, published in 2021, found that delirium among adults over the age of 65 years was associated with cognitive decline. This decline consisted of an average 1.8-point reduction on the Mini-Mental State Examination (95% CI –3.5 to –0.2) and an increased risk of new dementia diagnosis at the 12-month follow-up (OR 8.8, 95% CI 1.9–41.4) in individuals with delirium compared with individuals without delirium 16 . This study also found that greater delirium exposure (that is, recurrent episodes, or episodes of greater severity or longer duration) was associated with a greater risk of dementia and worse cognitive outcomes. A recent meta-analysis also reported a significant association between delirium and long-term cognitive decline (OR 2.30, 95% CI 1.85–2.86) 56 . These observations further support an association between delirium and subsequent cognitive decline and dementia. However, whether a causal mechanism underlies this observed association is not yet clear. If a causal relationship between delirium and dementia is identified, delirium might be a modifiable risk factor for dementia. An important next step will be to further explore the mechanisms that are shared by both delirium and dementia 57 .

Delirium and dementia: shared biomarkers

Biomarkers are playing an increasingly important role in advancing the mechanistic understanding of delirium. To date, most of the fluid biomarker studies in delirium and dementia have used cerebrospinal fluid (CSF) or blood (plasma or serum). Although CSF is thought to more accurately represent processes occurring in the brain, the collection of CSF, particularly in people with delirium, over multiple time points or in large-scale studies holds particular challenges 58 – 62 . Blood-based biomarkers are more accessible during acute illness, but plasma concentrations of biomarkers are often very low. Fortunately, with the development of ultrasensitive immunoassays, the detection of femtomolar concentrations of protein analytes has made it possible to examine a much wider range of potential biomarkers.

A previous systematic review identified 113 delirium biomarker studies that aligned with the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework 63 , which defines AD using biomarkers that reflect underlying pathological processes 64 . Many of these studies focused on inflammatory cytokines and about 20% of studies explored known AD biomarkers such as amyloid, tau and/or markers of neurodegeneration. A subsequent systematic review of biomarkers of delirium, published in 2021, found insufficient evidence to support the use of any single biomarker as a diagnostic or prognostic marker for delirium 37 ; however, a number of biomarkers did show promise for providing a better understanding of the pathophysiology of delirium.

Our intention for this review is to focus on the interface between delirium and dementia and, in our search for biomarkers shared between delirium and dementia, we opted for a direct approach by reviewing studies of biomarkers in delirium that either involved some participants with AD, including preclinical AD (that is, asymptomatic individuals identified by the presence of AD biomarkers), or that measured traditional AD biomarkers (see review criteria for details). We chose to concentrate on AD as it is the most common type of dementia 7 and the one for which the most evidence exists on the inter-relationship with delirium. The underlying pathophysiology of delirium is complex, with evidence supporting the involvement of a number of potential mechanisms, including neurodegeneration and neuronal injury, inflammation, disturbances in brain energy metabolism, disruption in neurotransmitter function, pharmacological effects, and failure of network connectivity 2 . Other pathways, including cortisol and the stress pathway, melatonin, and disruption of the sleep–wake cycle as well as the dopamine and cholinergic pathways, are also likely to contribute to the pathophysiology of delirium, but the specific contributions of these pathways 2 , 65 to the inter-relationship between delirium and dementia have not been explored in detail and were thus considered to be outside the scope of this Review.

Systemic inflammation

Systemic inflammation is thought to have a key role in the pathogenesis of delirium (see ref. 2 published in 2020 for a comprehensive review); however, studies have reported variable associations between plasma concentrations of the inflammatory markers CRP and IL-8 and risk of delirium 66 – 71 . A study by McNeil et al., which included participants with and without clinical dementia, found that plasma concentrations of IL-6, IL-8 and plasminogen activator inhibitor-1 (PAI-1) were associated with duration of delirium, but only among participants who did not have clinical dementia 66 (Table  2 ). A possible explanation for this finding is that people with dementia are more vulnerable to delirium than people without dementia. Therefore, people with dementia might become delirious without the occurrence of a substantial increase in inflammatory markers, whereas people without dementia might require a higher degree of systemic inflammation and endothelial dysfunction to develop delirium. In contrast, a single post-mortem study found higher levels of IL-6 in the brains of individuals with delirium than in the brains of individuals without delirium, and the presence of coexisting dementia did not affect these findings 72 .

Overview of potential plasma biomarkers shared between delirium and dementia

Note that studies differ in methods and reporting standards, definitions and measures for delirium and dementia used, varying study populations, and presence of different comorbidities. Therefore, we report only positive or negative associations and not effect sizes, which were not directly comparable across studies. Aβ, amyloid-β; AD, Alzheimer disease; DSD, delirium superimposed on dementia; ED, emergency department; IGF-1, insulin-like growth factor-1; MoCA, Montreal Cognitive Assessment; NA, not available; NfL, neurofilament light; PAI-1, plasminogen activator inhibitor-1; p-tau, phosphorylated tau; t-tau, total tau.

In animal studies, ample evidence indicates that systemic (peripheral) inflammation contributes to chronic neurodegenerative disorders via the activation of brain microglial cells 73 , 74 . In one study, wild-type mice and a mouse model of progressive neurodegeneration (ME7 prion disease) were challenged with the cytokine TNF 75 . Compared with wild-type mice, ME7 mice had increased sickness behaviour (considered to be an animal variant of delirium), impaired working memory performance, and higher levels of hippocampal and hypothalamic transcription of IL-1β, TNF, and CCL2 and translation of IL-1β. However, TNF did not result in substantial de novo pathology beyond the baseline level of neurodegeneration in ME7 animals 75 . In the APP/PS1 mouse model of AD, which expresses human amyloid precursor protein and a mutant version of human presenilin-1, secondary inflammatory insults (that is, infection or lipopolysaccharide challenge) were associated with an acute increase in production of IL-1β by microglia, which in turn triggered exaggerated levels of astrocytic chemokines and IL-6 (ref. 76 ).

In sum, the results of these studies suggest that the association between inflammatory markers and delirium is variable and that, in the presence of dementia pathology, the brain might be more vulnerable to developing delirium. The findings also support an association between systemic inflammation and neurodegeneration; however, systemic inflammation might affect the relationship between delirium and dementia in more than one way.

Neuroinflammation

Neuroinflammation is recognized as a prominent feature of AD pathology 77 . Microglial cells, the resident phagocytic cells of the brain, have many roles, including neuronal support, synaptic modulation and reorganization of neuronal circuitry. A post-mortem case–control study identified an increase in markers of microglial activity (HLA-DR and CD68) and astrocytosis (GFAP) in the brains of individuals with delirium compared with individuals without delirium; coexisting dementia did not affect this relationship 72 . The concentration of soluble TREM2 (triggering receptor expressed on myeloid cells 2) in the CSF is a surrogate measure of microglial function and has been found to be increased in prodromal and asymptomatic AD, with levels peaking in the mild cognitive impairment (MCI) stage, then declining during clinical dementia stages 78 . Similar to the IL-6 findings in the study by McNeil et al. 66 , a study by Henjum et al. found that higher CSF levels of soluble TREM2 were associated with a greater likelihood of delirium, but only among participants without clinical AD 79 . In this case, Henjum et al. speculated that people with clinical AD have constant activation of microglia by Aβ deposits and tau inclusions, and therefore the effect of delirium on microglial response is attenuated and the association is not observed (Table  3 ).

Overview of potential CSF biomarkers shared between delirium and dementia

Note that studies differ in methods and reporting standards, definitions and measures for delirium and dementia used, varying study populations, and presence of different comorbidities. Therefore, we report only positive or negative associations and not effect sizes, which were not directly comparable across studies. AD, Alzheimer disease; Aβ, amyloid-β; CSF, cerebrospinal fluid; DSD, delirium superimposed on dementia; ES, elective surgery; FABP3, fatty acid-binding protein 3; HF, hip fracture; NA, not available; NfL, neurofilament light; NSE, neuron-specific enolase; p-tau, phosphorylated tau; sTREM2, soluble fragment of triggering receptor expressed on myeloid cells; t-tau, total tau. a The ATN biomarker framework is used to distinguish AD from non-AD causes of cognitive impairment with three types of biomarkers: β-amyloid deposition (A), pathological tau (phosphorylated tau, T) and neurodegeneration (total tau, N) 64 . b Secretogranins associated with neurodegeneration. c Putrescine is elevated in AD and might be involved in amyloid plaque formation.

Disruptions to blood–brain barrier (BBB) integrity allow systemic inflammatory signals to reach the brain and have been observed in individuals with dementia 80 . One study assessed BBB disruption, as measured by Q-albumin (the ratio of CSF albumin to serum albumin), in a cohort of 120 patients with hip fracture. Ninety-one patients (76%) developed delirium or sub-syndromal delirium, of whom 59 (65%) had underlying dementia. No significant difference in the rate of BBB disruption was observed between the group of participants with dementia and those without dementia. However, all patients with BBB disruption ( n  = 14) had delirium ( n  = 11) or sub-syndromal delirium ( n  = 3), suggesting that this disruption might contribute to the development of delirium 81 . In a number of animal studies, orthopaedic surgery was associated with increased neuroinflammation, disruption of the BBB and impaired performance on tests of attention 82 , 83 . In mice, treatment with a broad spectrum anti-inflammatory agent was found to prevent surgery-induced BBB disruption, microglial activation and memory dysfunction 84 .

In summary, neuroinflammation is associated with both dementia and delirium separately. Similar to the data regarding systematic inflammation (discussed above), the influence of neuroinflammation on delirium in the presence of dementia pathology seems to be variable. Emerging data also support the hypothesis that BBB disruption is present in both delirium and dementia, which would enable more systemic inflammatory signals to reach the brain and exert their effects.

AD biomarkers and apolipoprotein E

The levels of amyloid-β (Aβ 1–42 ), total tau (t-tau) and phosphorylated tau (p-tau) in the CSF are known to reflect key elements of AD pathology, including the presence of extracellular Aβ plaques and intracellular neurofibrillary tangles (consisting of hyperphosphorylated tau protein) in cortical and limbic areas of the human brain 85 . AD is associated with lower CSF Aβ 1–42 levels and higher CSF tau levels 86 . These biomarkers have a central position in the 2018 NIA-AA biological definition of AD and AT(N) classification system, which groups biomarkers into those that reflect Aβ deposition (A), pathological tau (T) and neurodegeneration (N) 64 . Studies that examined these AD biomarkers in individuals with delirium have produced mixed results, but associations between delirium and CSF levels of tau and Aβ have been reported (Table  3 ).

In one study, low concentrations of Aβ 1–42 in CSF after elective hip surgery were predictive of delirium in patients without dementia 87 . Similarly, in another study of patients with hip fracture without dementia, lower CSF Aβ 1–42 and higher CSF t-tau levels were present in participants that developed delirium compared with participants that did not develop delirium 88 . This observation suggests that preclinical AD brain pathology is relevant to and might have a role in delirium pathophysiology. In a prospective observational cohort of older patients undergoing surgery, plasma p-tau concentrations were higher after surgery than before surgery, and this increase was significantly larger in participants with delirium than in participants without delirium 89 . After adjusting for age, sex, preoperative cognition and change in plasma IL-8 levels, the association between plasma p-tau concentration and delirium severity remained statistically significant. Another study reported that individuals with a lower CSF Aβ 1–42 to tau ratio, which is indicative of greater AD pathology, were more likely to have postoperative delirium than individuals with a higher CSF Aβ 1–42 to tau ratio 90 . One study identified an association between depression and an increased likelihood of postoperative delirium in older adults undergoing hip fracture repair 91 . In this study, CSF Aβ 1–42 to t-tau and Aβ 1–42 to p-tau181 ratios were inversely associated with higher depression scores, suggesting that depression is associated with underlying AD pathology and postoperative delirium. In contrast, another study of older adults with hip fracture did not find significant differences in preoperative concentrations of Aβ 1–42 , t-tau and p-tau in the CSF between participants with and without delirium 92 (Tables  2 and ​ and3 3 ).

The ε4 allele of the gene encoding apolipoprotein E ( APOE ) is a known risk factor for AD, but whether it is also a risk factor for delirium is unclear. A number of studies have identified an association between APOE ε4 and the risk of delirium 93 – 95 , whereas other studies found no such association 70 , 96 . In one study of older adults without dementia undergoing elective surgery, a strong relationship between a high concentration of plasma CRP and delirium incidence was identified in carriers of at least one APOE ε4 allele, but this association was not observed among non-carriers 68 . This finding suggests that gene–protein interactions might modify inflammation, thereby representing an indirect link between delirium and dementia. A study of patients undergoing surgical repair of hip fracture found that lower plasma levels of IGF-1 and absence of the APOE ε4 allele predicted delirium recovery 70 (Table  2 ).

Animal models have been used to test the hypothesis that postoperative delirium results from disruption of the BBB by neuroinflammation and neurovascular dysfunction and that the brain is more susceptible to such changes in the setting of pre-existing AD pathology. One model that has been used for this purpose is the APPSwDI/NOS2 −/− mouse line, which is a cross between a line of mice that develops Aβ protein deposits and a line of mice with nitric oxide synthase 2 (NOS2) knockout. This model, also referred to as the CVN-AD model, has a phenotype of impaired spatial memory, extensive tau pathology, dense microvascular amyloid plaques, and statistically significant neuron loss in the hippocampus and subiculum 97 . In one study, tibial fracture surgery was performed on 12-month-old CVN-AD mice. Compared with naive mice, mice that had undergone surgery had distinct neuroimmune and vascular impairments, including increased levels of neuroinflammatory markers, such as G‐CSF, IL‐6, IL-1β, TNF, monocyte chemoattractant protein 1 (MCP1) in plasma, acute microgliosis in the hippocampus and cortex, and Aβ deposition in the hippocampus 98 . Increased expression of aquaporin 4 (AQP4), a marker of neurovascular dysfunction, was also observed in mice that had undergone surgery. These changes were accompanied by impaired performance on a serial reaction time task, a measure of attention and a core feature of delirium-like behaviour in animal models.

The results of the studies discussed here suggest three possible relationships between delirium and dementia. First, most but not all studies support an association between the presence of AD biomarkers and delirium incidence. This suggests that underlying AD pathology, even in the absence of cognitive impairment (that is, preclinical dementia), might influence the development of delirium. Second, work examining the relationship between APO E genotype and delirium suggests that there might be gene–protein interactions that modify inflammation in patients with the APO E ε4 allele who develop delirium. Last, evidence from the CVN-AD animal model further supports a role of neuroinflammation in both delirium and dementia.

Neuronal injury

Emerging data from studies of patients with delirium and patients with DSD indicate an association between neuronal injury markers and delirium, but whether neuronal injury creates a permissive ‘condition’ for delirium occurrence, or is a consequence of delirium, is not yet known. Early work focused on plasma levels of S100B, which is a calcium-binding protein that is found primarily in astrocytes and can easily cross the BBB, and neuron-specific enolase (NSE), which is a cytoplasmic enzyme found in neurons and neuroendocrine cells. This work yielded mixed results, with some studies finding associations between elevated serum S100B and delirium 99 – 101 and others finding no association between CSF S100B and delirium 102 . One study that did find an association between S100B and delirium observed this association only in participants with p-tau levels consistent with dementia 99 . In another study, serum S100B levels were associated with delirium but also correlated with levels of IL-6 and IL-8, suggesting that neuroinflammation owing to delirium could be related to neuronal injury 101 .

In a study published in 2018, CSF levels of neurofilament light (NfL), a marker of neuroaxonal injury, were higher among patients with hip fracture who developed delirium than those who did not develop delirium 103 . Whether this increase in NfL is a result of underlying neurodegeneration or secondary to a delirium-associated reaction that triggers neuronal injury is unclear. A more recent study of older adults undergoing elective surgery found that plasma NfL levels increased gradually during the 4 days after surgery in all patients, although the increase in NfL was more profound in patients with delirium 104 . We also performed a study in a cohort of older adults without dementia undergoing elective surgery and found that patients who had higher levels of plasma NfL before surgery were more likely to develop delirium 105 . Furthermore, those with the highest plasma NfL levels at baseline had more severe delirium than those with the lowest plasma NfL levels. Compared with baseline, plasma NfL levels were increased on postoperative day 1 and this increase was more pronounced in patients with delirium than in patients without delirium. At 1 month after surgery, plasma NfL levels remained elevated, and higher NfL levels were associated with a greater likelihood of delirium during hospitalization and a greater degree of cognitive decline at the 1-month time point 105 . These findings suggest that NfL could be useful as a predictive biomarker for delirium risk and long-term cognitive decline and, once confirmed, would provide pathophysiological evidence for neuroaxonal injury after delirium. However, these results should be interpreted with caution as increased levels of plasma NfL can also arise from damage to the peripheral nervous system 106 as well as general anaesthesia and surgery 107 .

In a study of patients with hip fracture, increased levels of lactate and reduced levels of NSE in the CSF were observed in individuals with delirium compared with individuals with dementia 102 . Lactate production is increased by impaired tissue oxygenation, and NSE, an isoform of the glycolytic enzyme enolase, leaks into the extracellular space during cellular injury or death. The authors of the study speculated that, in delirium, changes in metabolism result in increased levels of CSF lactate, which induces secondary suppression of NSE levels, and that lactate has a greater role in delirium than NSE. Fatty acid-binding protein 3 (FABP3) is a cytoplasmic transport protein for fatty acids and other lipophilic substances. FABP3 has been linked to metabolic and inflammatory pathways and is considered a non-specific marker of neurodegeneration. FABP3 is released into the CSF in neurodegenerative disorders and after brain injury, and CSF levels were found to be elevated after hip fracture in older adults 108 . However, FABP3 levels were not associated with delirium. These results suggest that neuronal injury reflected by FABP3 might be distinct from processes involved in delirium 108 (Tables  2 and ​ and3 3 ).

In summary, the data on injury markers — neuronal, astrocytic and glial — are mixed. Brain cell injury might increase the risk of delirium, and delirium itself might then lead to additional injury and release of injury markers. The presence of underlying neuroinflammation or AD pathology might also be associated with cellular injury, suggesting that multiple injury pathways are involved in the relationship between delirium and dementia (Table  2 ). Further studies are needed to establish the presence of a causal relationship between delirium, neuronal injury and cognitive impairment.

In a study published in 2019, PAI-1, which promotes fibrinolysis and contributes to endothelial dysfunction, was measured in the plasma of a group of older adults admitted to hospital. Higher PAI-1 levels were associated with longer duration of delirium, but only among patients without dementia 66 . This observation suggests that, similar to the findings regarding IL-6, delirium might be precipitated by lower levels of PAI-1 in people with dementia than in people without dementia. Neurogranin is a postsynaptic calmodulin-binding protein commonly found in the hippocampus and cerebral cortex and involved in synaptic regeneration and plasticity. A meta-analysis found that CSF neurogranin concentration can predict cognitive decline in individuals with MCI 109 ; however, in a study of patients with hip fracture with and without delirium and patients with AD, CSF levels of neurogranin were not associated with delirium or with DSD 110 . Diazepam-binding inhibitor has been proposed as a biomarker of neuroinflammation as it binds to translocator protein (TSPO) and reflects microglial activation and neuroinflammation 111 . In a small study, the average CSF level of diazepam-binding inhibitor was higher in patients with dementia than in healthy controls and higher in patients with delirium than in patients with dementia 111 (Table  3 ). Further study of these potential mechanisms is required.

Proteomics and metabolomics

Proteomic and metabolomic studies can either use an exploratory, non-hypothesis-driven approach or a targeted approach that assesses the expression of genes or proteins that are already known to be involved in the pathogenesis of a disease. In one exploratory proteomic project, investigators compared CSF from participants with delirium with CSF from participants with mild AD. Delirium was associated with increased levels of proteins involved in neurodegeneration and inflammation, such as α1-acid glycoprotein, α2-macroglobulin and fibrinogen 112 , and decreased levels of chromogranins and secretogranins. α1-Acid glycoprotein upregulation was confirmed by ELISA. The researchers also compared the control participants with mild AD to those with moderate AD and found that many of the proteins dysregulated in delirium were unaffected in moderate AD, suggesting that there are distinct pathways occurring in delirium and dementia. A targeted metabolomic study of preoperative CSF samples found that polyamines, specifically spermidine, glutamine and putrescine, were elevated in patients who developed postoperative delirium compared with those who did not 113 . Although this study excluded patients with clinical dementia, other evidence indicates that polyamines are also elevated in AD and might be involved in the formation of Aβ plaques 114 , 115 . Future proteomic and metabolomic studies could identify biomarkers and pathways that are associated with the inter-relationship between delirium and dementia (Table  3 ).

Neuroimaging

Structural and functional neuroimaging biomarkers have been studied extensively in dementia and an increasing number of studies have examined these markers in delirium in older adults without dementia 116 . A growing number of studies in the past several decades have identified predictors of delirium, such as underlying brain atrophy 117 and white matter intensities 118 , 119 , or correlates of delirium such as reduced cerebral flood flow 120 , 121 and changes in functional connectivity 122 . The ‘AD signature’ refers to the reduction in cortical thickness in a specific set of brain regions that has been used as a structural biomarker of AD and is associated with cognitive decline and progression to dementia 123 . One study examined the link between delirium and the AD signature by performing preoperative MRI scans in a cohort of older adults undergoing elective surgery 124 . A thinner cortex in the AD signature regions did not predict delirium incidence, although cortical thinning was associated with greater delirium severity among those who developed delirium. This finding suggests that cortical atrophy, possibly as a result of underlying neurodegeneration owing to preclinical AD, might serve as a vulnerability factor that increases severity once delirium occurs.

Functional network connectivity studies have identified lower connectivity strength and network efficiency in patients with AD 125 or with amnestic MCI 126 compared with healthy controls as well as a loss of efficiency and local clustering in individuals with delirium compared with those without delirium 127 . These observations support the hypothesis that brain network dysconnectivity is a final common pathway for delirium 122 , 128 . A limited number of studies have performed neuroimaging in individuals with DSD. In one study, each participant underwent an [ 18 F]fluoro-2-deoxyglucose PET scan during the delirium episode and again after hospital discharge and resolution of delirium. Global hypometabolism was observed during delirium whereas, after delirium resolution, higher metabolism was observed globally and specifically in the posterior cingulate cortex 129 . Anatomically, the posterior cingulate cortex is important as a central node in the default network and is involved in diverse brain functions, including cognition, attention and arousal 130 . Studies have reported early amyloid deposition 131 and reduced metabolism 132 in this region in individuals with AD. Another study reported increased functional connectivity between the posterior cingulate cortex and dorsolateral prefrontal cortex and reversible reduction of functional connectivity of subcortical regions in participants with ongoing delirium compared with participants without delirium and participants who had recovered from delirium 122 . In a small study ( n  = 16) of older patients with hip fracture without dementia, participants who experienced postoperative delirium ( n  = 5) all had negative PET-amyloid findings and 6 of the 11 participants without postoperative delirium had positive PET-amyloid findings on scans acquired 3–5 months after recovery from surgery 133 (Table  4 ). These findings suggest that preclinical amyloid pathology does not contribute to an increased risk of delirium after non-elective surgery, and further study is warranted.

Overview of potential biomarkers shared between delirium and dementia: neuroimaging and neurophysiological studies

Note that studies differ in methods and reporting standards, definitions and measures for delirium and dementia used, varying study populations, and presence of different comorbidities. Therefore, we report only positive or negative associations and not effect sizes, which were not directly comparable across studies. AD, Alzheimer disease; DLPFC, dorsolateral prefrontal cortex; DSD, delirium superimposed on dementia; PCC, posterior cingulate cortex.

In summary, neuroimaging biomarkers have identified both structural and functional predictors of delirium. Some but not all neuroimaging markers of AD were also associated with delirium. The results of a functional imaging study of patients with DSD suggest that changes occur in network connectivity, particularly the posterior cingulate cortex, during an episode of delirium.

Transcranial magnetic stimulation, Doppler and EEG

A number of novel, innovative biomarkers of brain activity have shown promise in understanding the interface of delirium and dementia. Transcranial Doppler is a non-invasive technique that uses ultrasound to measure the velocity of flow through blood vessels in the brain. One study used this approach to measure flow velocity (FV) in the middle cerebral artery in individuals with DSD, dementia or delirium as well as a cognitively healthy control group 120 . Compared with the other groups, statistically significant reductions in FV were observed in participants with delirium or DSD, with the lowest FV observed in the group of participants with DSD. Of note, among participants with delirium, FV increased once the delirium resolved.

Changes in EEG spectral power and connectivity — specifically, EEG slowing characterized by increases in delta and theta band frequencies and decreases in alpha band frequencies — have been identified in patients with preclinical AD 134 , MCI 135 and AD 136 , 137 in comparison with cognitively healthy controls. A systematic review of the literature on EEG and delirium reported that delirium in adults is consistently associated with EEG slowing and decreased alpha band EEG connectivity 127 , 138 . Similarly, a study identified a correlation between intraoperative frontal alpha power and preoperative cognitive function in older adults 139 , and an intraoperative processed EEG-based measure of lower brain anaesthetic resistance was associated with increased postoperative delirium risk in older patients undergoing surgery 140 . However, additional research is needed to understand how this finding relates to DSD. One conceptual model theorizes that delirium occurs from disruption of normal brain function secondary to impairments in brain connectivity and plasticity; this hypothesis could be tested using transcranial magnetic stimulation and EEG 138 , 141 .

In summary, markers of brain physiology are beginning to reveal how changes in cerebral blood flow, spectral power and connectivity can be associated with delirium; however, further work is needed to expand these findings to patients with DSD.

Delirium prevention in persons with dementia

Multidisciplinary, multicomponent, non-pharmacological interventions have been developed for delirium prevention. These interventions include the Hospital Elder Life Program (HELP) 33 , 142 and the ABCDEF bundle 143 , which have been found to reduce the incidence and duration of delirium and reduce functional decline in older patients 13 . The interventions vary in the number of components included, but most include individualized care, education, reorientation and early mobilization. A meta-analysis of 8 studies, involving a total of 2,105 participants, reported that multicomponent interventions reduce the incidence of delirium (RR 0.53, 95% CI 0.41–0.69, I 2  = 0). HELP includes interventions specifically for use in persons with dementia (Table  5 ), but their effectiveness in this population is not yet clear. A systematic review that assessed the effectiveness of delirium prevention in individuals with dementia identified seven studies that met inclusion criteria 144 . Using the GRADE framework for the evaluation of study quality, three studies were determined to be of moderate quality and four of low quality. Both studies with moderate grade evidence (that is, the true effect is probably close to the estimated effect) — one study using pre-printed delirium-friendly postoperative orders 145 and another using a multidisciplinary postoperative intervention 146 — reported significant reductions in delirium incidence compared with usual care. In terms of pharmacological intervention, in a single 2-year, open-label study comparing rivastigmine with aspirin in patients with vascular dementia, significantly fewer participants in the rivastigmine group developed delirium 147 . However, a subsequent multicentre, double-blind, placebo-controlled randomized trial found that rivastigmine did not reduce delirium duration and the trial was halted early due to increased mortality in the rivastigmine group 148 .

Suggested adaptations to delirium prevention interventions for individuals with dementia

A major limitation of the studies discussed here is the lack of high-grade evidence owing to variability in how delirium and dementia are defined in the study, the inclusion of more than one type of dementia, small sample sizes and the use of case–control study designs 144 . Another limitation is that a number of delirium prevention trials have been conducted using ‘cognitive impairment’, as defined by performance on a cognitive screening test, instead of a clinical diagnosis of dementia 149 , 150 . One study, which found that use of HELP was associated with a significant reduction in delirium incidence, did include persons with dementia, but the effect of the prevention was not examined in this subgroup 142 . More definitive delirium prevention trials in persons with dementia are needed and are under way. For example, the PREvention Program for Alzheimer’s RElated Delirium (PREPARED) cluster randomized trial, which aims to assess the effect of a multicomponent intervention on the incidence of delirium, severity of delirium episodes, duration of delirium episodes, and number of delirium episodes among persons with dementia and/or cognitive impairment residing in a long-term care facility 151 .

In summary, most delirium prevention strategies focus on minimizing one or more modifiable delirium risk factors via a non-pharmacological, multidisciplinary approach 142 , 152 , 153 . Whether and how prevention strategies might address specific pathophysiological mechanisms remains unknown and presents an important area for future research.

A hypothetical model

Taken together, the evidence discussed here indicates that the inter-relationship between delirium and dementia is likely to be complex (Fig.  1 ). Delirium might be the expression of the balance between vulnerability (that is, the factors predisposing towards the development of delirium) and resilience (that is, the ability to maintain function in the setting of an insult or precipitating factors). In this model, patients who are highly vulnerable to delirium because of factors such as underlying neurodegeneration or abnormal neuroinflammation develop delirium only when resilience factors, for example, cognitive reserve, can no longer maintain healthy functioning. The development of delirium might then result in acceleration of the underlying neurodegeneration, perhaps via inflammation or gene interactions with inflammation. Alternatively, in some individuals, delirium itself might be associated with neuronal injury 103 , 105 , with ‘de novo’ mechanisms then leading to dementia.

a , b | In the setting of precipitating factors, such as hypoxia, metabolic abnormalities, medications, infection or surgery, and in the presence of an existing vulnerability, such as Alzheimer disease (AD) or other neurodegenerative pathology, cerebrovascular disease, or injury, delirium (green) can occur. Alternatively, owing to the presence of resilience factors, such as cognitive reserve, or the implementation of prevention strategies (grey) to minimize one or more modifiable delirium risk factors, delirium does not occur (red). c | The development of delirium and subsequent neuroinflammation might then result in the acceleration of underlying neurodegenerative pathology. Alternatively, in individuals without underlying neurodegenerative pathology, delirium might be associated with neuronal injury, with ‘de novo’ mechanisms leading to dementia.

These hypotheses could be tested by measuring a biomarker of brain vulnerability prior to exposure to a precipitant and determining if biomarker levels are predictive of incident delirium. Next, a biomarker of neuroinflammation could be measured during the delirium episode and an association with incident delirium or delirium severity could be tested for. Last, a biomarker of neuronal injury, such as NfL, could be measured during the delirium episode to test for an association with incident delirium and delirium severity as well as after the delirium episode to test for an association with outcomes of delirium. To date, a causal relationship between delirium and neuronal injury has not been established.

A major challenge in understanding the relationship that exists between delirium and dementia is that the underlying pathology for each condition is complex and involves multiple mechanistic pathways. As discussed above, potential pathophysiological mechanisms in delirium include neurodegeneration and neuronal injury, inflammation, disturbances in brain energy metabolism, disruption in neurotransmitter function, effects of pharmacological agents, and failure of network connectivity. For dementia, although we have focused on studies of AD, possible contributions from mixed dementia pathology (that is, AD and cerebrovascular disease) must also be considered. Furthermore, some patients with AD biomarkers did not develop delirium after surgical treatment of hip fracture 91 , 92 , suggesting that the presence of AD pathology does not guarantee the development of delirium in response to this precipitant. Review of the existing literature on delirium biomarkers found that many studies either did not include known AD biomarkers, the quality of biomarker data was moderate or had a high risk of bias, or the cognitive data was limited 63 .

Adding further complexity to the delirium–dementia inter-relationship is that both delirium and dementia exist along a continuum, with stages of AD ranging from preclinical AD, defined as the presence of pathological AD biomarkers in cognitively healthy individuals, to mild, moderate and severe stages of cognitive impairment. The term sub-syndromal delirium refers to the acute or subacute onset of delirium symptoms, including disturbed attention and other cognitive and/or neuropsychiatric disturbances, in the absence of full syndromal delirium but not better accounted for by another neuropsychiatric condition 154 . Sub-syndromal delirium sometimes progresses to delirium, which itself varies in severity. Thus, future studies examining the inter-relationship between delirium and dementia must address these issues by incorporating novel biomarkers into thoughtfully designed studies.

Delirium in an ageing population

Our knowledge and understanding of delirium pathophysiology have advanced, but much still needs to be learned about the relationship between delirium and dementia. The number of people with dementia worldwide already exceeds 5 million and, as the global population ages, this figure is expected to reach 152 million by 2050 (ref. 8 ). Likewise, because dementia is such a strong risk factor for delirium and because delirium is common among older adults, delirium and dementia will clearly continue to be substantial public health issues. This increasing burden on health-care systems highlights the imperative for future research. Efforts to refine the consensus definition of delirium, harmonize instruments for measuring delirium and delirium severity, advance our understanding of delirium pathophysiology, and develop novel prevention and treatment strategies 155 are ongoing. However, research efforts with the same goals should also be adapted and directed towards the interface between delirium and dementia (Box  1 ).

One particularly important area for future research is the examination of the effects of delirium prevention on dementia incidence and rate of progression. Our prior work found that, among persons with dementia, an episode of delirium was associated with a threefold increase in the rate of cognitive decline 20 . Delirium prevention is an intervention that has been shown to be effective and is already readily available; thus, studies that directly quantify the benefit of delirium prevention on the cognitive trajectory in AD are greatly needed.

Box 1 Priorities for advancing the understanding of the interface between delirium and dementia

Define and measure

• Develop consensus approaches, precise diagnostic criteria and comprehensive guidelines for the assessment and diagnosis of delirium superimposed on dementia (DSD)
• Use standardized reference criteria for diagnosis
• Establish standardized, well-validated DSD measurement instruments for clinical and research use
• Define the association between delirium and specific neuropsychological deficits
• Identify underlying contributors by incorporating biomarkers and pathophysiological indicators into studies
• Develop core outcomes for use in clinical trials

Understand pathophysiology

• Develop animal models to test potential pathophysiological mechanisms of DSD
• Use standardized preclinical or mechanistic protocols to enable harmonization across studies
• Incorporate novel fluid, neuroimaging and neurophysiology biomarkers
• Apply innovative approaches, such as systems biology, multi-omics and machine learning to analyse data
• Use study designs that consider dementia and delirium mechanisms, both individually and together

Prevent and treat

• Implement novel evidence-based approaches
• Use multicomponent and sequential treatment approaches. Apply known effective approaches for delirium prevention and test effectiveness for slowing long-term cognitive decline
• Follow adaptive trial design to enable modifications in interventions and/or study population
• Engage pragmatic trials in multiple settings (that is, acute hospital, rehabilitation, long-term care)
• Measure effects of delirium prevention and treatment on dementia severity and progression

Promote awareness

• Increase awareness through public education
• Prioritize research funding
• Define social and economic impact of DSD

Conclusions and future directions

Delirium and dementia are common conditions in older adults, often occurring together as DSD. However, DSD often goes undetected or is assumed to be part of the underlying dementia. Recognition of the presence of an acute change from baseline or of symptoms specific to delirium or dementia might aid in the detection of delirium in a person with dementia. Two major challenges of developing screening and diagnostic instruments for DSD are the varying severity of the underlying cognitive impairment and the lack of a reliable reference standard. In 2020, two working groups published roadmaps of research priorities in delirium 57 , 155 , with goals of improving patient care and clinical outcomes, developing better prevention and treatment strategies, and advancing our understanding of the biology of delirium and the inter-relationship between delirium and dementia. As the number of older adults — and thus the number of individuals at risk of delirium — is growing and the evidence supporting delirium as a risk factor and possible trigger for age-related brain disorders is accumulating, there has been a heightened effort to facilitate the recognition and treatment of delirium. For example, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) is a collaborative, interdisciplinary network of investigators across more than 27 institutions worldwide and aims to advance scientific research on the causes, mechanisms, outcomes, diagnosis, prevention and treatment of delirium in older adults. Another global delirium campaign, the International Drive to Illuminate Delirium (IDID) 57 , aims to advance the field of delirium along the pillars of diagnosis, awareness, burden, biology and policy to ultimately lessen the physical and cognitive burden of delirium. This campaign recognizes that delirium is an important risk factor and a potential trigger for cognitive, motor and mood disorders in older adults and that delirium and accelerated cognitive decline might unmask pre-existing preclinical dementia pathology and thereby reduce the time to onset of clinical dementia. Therefore, delirium is increasingly recognized as an important and unexplored opportunity for dementia prevention 57 .

With the awareness that delirium is a risk factor for dementia, improving the care of individuals with delirium must become a key focus of public health efforts 57 . Global public health awareness campaigns that recognize the potential role of delirium as a risk factor and trigger for new dementia and acceleration of cognitive decline will hopefully aid in achieving a better understanding of DSD. Such campaigns could also help identify the extent to which delirium is a potentially modifiable risk factor for dementia and whether delirium and dementia have shared mechanisms. Although delirium has traditionally been considered a geriatric syndrome, re-conceptualizing delirium as a neurological condition and increasing the focus on aetiology and subsequent neuropathophysiology 156 , 157 would help further advance our understanding of the relationship between delirium and dementia.

Evidence from biomarker studies supports a role of systemic inflammation, neuroinflammation and neuronal injury in delirium pathophysiology. Whether underlying factors, such as preclinical dementia, make the brain more vulnerable and thus more likely to lose the ability to function normally in the face of infection or trauma, with the end result being an episode of delirium, or if delirium itself causes neuronal injury and death, remains unknown; however, both of these possibilities are supported by emerging data. Important advances in plasma and CSF biomarkers, animal models of neuroinflammation, functional and structural MRI, and novel neurophysiology markers hold great promise for advancing the field. Future research should use standardized methods for defining and measuring the severity of delirium and dementia, and universal reporting standards for cognitive and functional outcome measures to enable harmonization of the resulting data. Studies should be conducted in a range of study populations and in the presence of different comorbidities to ensure that the findings are generalizable.

The SARS-CoV-2 pandemic has resulted in a substantially increased rate of delirium 158 , 159 both directly, via the effects of COVID-19, and indirectly owing to the subsequent inability to implement normal delirium prevention strategies 160 . Initial estimates of delirium among patients with COVID-19 ranged from 11% among hospitalizations in Northern Italy 158 to 84.3% in two intensive care units in France 157 ; however, a 2021 multi-site, large, international cohort study of more than 2,000 patients who had severe COVID-19 from February to August 2020, found that 54.9% were delirious for a median of 3 days 161 . Evidence suggests that COVID-19-associated delirium might eventually be more widespread, more severe and associated with more adverse outcomes than previously seen with delirium and post-intensive care unit syndrome (Box  2 ). An observational cohort study found dementia to be a statistically significant risk factor for COVID-19 (ref. 162 ) and for increased mortality with COVID-19 (ref. 163 ). Delirium can also be the presenting symptom of COVID-19 among individuals with dementia 163 . Studies of COVID-19-associated delirium should be a priority for future research efforts. These studies should focus on the role of inflammation and neuroinflammation, rates of incident dementia and other cognitive and functional outcomes, and strategies for cognitive rehabilitation and delirium prevention.

Established clinical guidelines focus on improving the diagnosis of delirium and reducing hospital stays and complications 14 , 164 , 165 , but they do not directly address delirium in persons with dementia. Therefore, the development of specific clinical guidelines for the diagnosis and management of DSD is needed. We hope that, through a unified public health approach, these guidelines can effectively reduce the burden, severity and progression of dementia through delirium prevention.

Box 2 Special challenges of COVID-19 in persons with delirium superimposed on dementia

Individuals with pre-existing cognitive impairment and dementia are at increased risk of serious COVID-19 infection and more severe complications than those without cognitive impairment and dementia. In particular, individuals with dementia have:

• Increased risk of delirium with COVID-19 infection 169
• Increased risk of atypical presentation of COVID-19 infection, such as delirium, falls, functional decline and failure to thrive, in the absence of fever, shortness of breath and cough; this feature can lead to a lack of recognition of COVID-19 infection 170 , 171
• Increased risk of COVID-19 causing serious illness and mortality 163 , 172 , 173
• Increased risk of long-term neurocognitive sequela of COVID-19 (refs. 174 , 175 )

Recommendations for assessment and management of COVID-19 in individuals with dementia:

• Screen for COVID-19 in older adults presenting for urgent medical care, even in the absence of typical symptoms 170
• Limit use of deliriogenic medications when treating individuals with dementia for COVID-19 (ref. 161 )
• Care providers in full personal protective equipment can wear a tag with their name and a photograph visible to patients
• Connect patient with family by teleconferencing
• Enhance mobilization by providing instructions for in-room and bed range-of-motion exercises

Acknowledgements

This work is dedicated to the memory of Joshua Bryan Inouye Helfand. Both authors have received grants from the National Institute on Aging.

Author contributions

The authors contributed equally to all aspects of the article.

Peer review

Peer review information.

Nature Reviews Neurology thanks Leiv Otto Watne, who co-reviewed with Mari Aksnes; Miles Berger; Barbara van Munster; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

A PubMed search was conducted using the keywords: Alzheimer’s disease, dementia, delirium AND biomarkers. Articles were then reviewed to find original studies, which either enrolled persons with dementia, including preclinical dementia (that is, asymptomatic persons identified by the presence of Alzheimer disease biomarkers), or which measured traditional Alzheimer disease biomarkers. Additional original research studies identified from review articles, including Wilson et al. 2 and Dunne et al. 37 , were included. This search was not intended to be a systematic review and it is possible that some articles may have been missed.

Related links

Network for Investigation of Delirium: Unifying Scientists (NIDUS): http://www.deliriumnetwork.org/

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