What is major neurocognitive disorder (dementia), including its definition, etiology, risk factors, clinical features, diagnostic criteria, and management?

Major Neurocognitive Disorder (Dementia): Comprehensive Overview

Definition and Core Diagnostic Criteria

Major neurocognitive disorder (dementia) is diagnosed when cognitive or behavioral symptoms interfere with the ability to function at work or usual activities, represent a decline from previous functioning, are not explained by delirium or major psychiatric disorder, and involve impairment in at least two cognitive domains. 1, 2

The diagnosis fundamentally requires three essential elements 2:

• Functional impairment: Cognitive or behavioral symptoms must interfere with ability to function at work or usual activities, requiring at minimum assistance with complex instrumental activities of daily living such as paying bills or managing medications 1, 2
• Documented decline: Symptoms must represent a decline from previous levels of functioning and performing 1, 2
• Exclusion of other causes: Symptoms are not explained by delirium or major psychiatric disorder 1, 2

Cognitive Domain Assessment

Cognitive impairment must be detected through both history-taking from the patient and a knowledgeable informant and objective cognitive assessment (bedside mental status examination or neuropsychological testing) 1, 2. Neuropsychological testing should be performed when routine history and bedside examination cannot provide a confident diagnosis 1.

The cognitive or behavioral impairment must involve a minimum of two of the following five domains 1, 2:

1. Memory Impairment (Learning and Recall)

• Repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on familiar routes 1

2. Executive Dysfunction

• Poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities 1

3. Visuospatial Impairment

• Inability to recognize faces or common objects, inability to find objects in direct view despite good acuity, inability to operate simple implements, difficulty orienting clothing to the body 1

4. Language Dysfunction

• Difficulty thinking of common words while speaking, hesitations, speech/spelling/writing errors 1

5. Behavioral and Personality Changes

• Uncharacteristic mood fluctuations, agitation, impaired motivation, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, socially unacceptable behaviors 1

Critical Distinction: Major vs. Mild Neurocognitive Disorder

The differentiation of dementia from mild cognitive impairment (MCI) rests entirely on whether there is significant interference in the ability to function at work or in usual daily activities. 2

Mild Cognitive Impairment (MCI) Criteria 1:

• Cognitive concern reflecting a change in cognition reported by patient, informant, or clinician 1
• Objective evidence of impairment in one or more cognitive domains 1
• Preservation of independence in functional abilities (may have mild problems with complex tasks but maintains independence) 1
• Not demented 1

Etiology and Major Subtypes

Alzheimer Disease (Most Common)

Alzheimer disease affects 5.8 million people in the United States and is the most common cause of dementia 3. The typical presentation includes 1:

• Amnestic presentation (most common): Impairment in learning and recall of recently learned information, plus dysfunction in at least one other cognitive domain 1
• Non-amnestic presentations: Language-predominant, visuospatial-predominant, or executive dysfunction-predominant 1, 2
• Insidious onset with gradual progression over months to years 1

Vascular Dementia

The second most common form of dementia, often co-occurring with other progressive cognitive disorders 4. Characterized by substantial cerebrovascular disease with history of stroke temporally related to cognitive onset, or multiple/extensive infarcts, or severe white matter hyperintensity burden 1.

Lewy Body Dementias

Encompasses Parkinson disease dementia and dementia with Lewy bodies, differentiated primarily by the order of motor and cognitive symptom onset 4. Rivastigmine can be used to treat symptomatic Parkinson disease dementia 3.

Frontotemporal Dementia

Occurs earlier than other forms, progresses rapidly, and often has a genetic component 4. Personality and behavioral changes as the primary presenting features strongly suggest behavioral variant frontotemporal dementia rather than Alzheimer disease 5. Notably, memory is often preserved early in the disease course 6.

Mixed Dementias

Dementia is commonly associated with more than one neuropathology, usually Alzheimer disease with cerebrovascular pathology 3.

Diagnostic Evaluation Algorithm

Step 1: Obtain Detailed History

Obtain detailed information about cognitive concerns from both the patient and a knowledgeable informant, focusing on 2:

• Onset (insidious vs. sudden)
• Progression pattern (gradual vs. rapid)
• Impact on instrumental activities of daily living 2

Step 2: Cognitive Assessment

Use standardized cognitive screening tools such as the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) 2. If assessment is inconclusive (symptoms present but normal examination findings), neuropsychological testing can help determine whether dementia is present 3.

Step 3: Physical Examination

Physical examination may help identify the etiology of dementia 3:

• Focal neurologic abnormalities suggest stroke 3
• Motor examination findings may indicate Parkinson's spectrum disorders 6

Step 4: Neuroimaging

Brain MRI is superior to CT for detecting focal atrophy patterns characteristic of dementia subtypes 6. Neuroimaging may demonstrate structural changes including focal atrophy, infarcts, and tumors that may not be identified on physical examination 3.

Step 5: Additional Testing (When Indicated)

Consider cerebrospinal fluid assays or genetic testing in atypical dementia cases 3:

• Age of onset younger than 65 years 3
• Rapid symptom onset 3
• Impairment in multiple cognitive domains but not episodic memory 3

Biomarker Evidence (Research and Specialty Settings)

Biomarkers may increase certainty that the clinical dementia syndrome is due to Alzheimer disease pathophysiology 1:

Amyloid-Beta Biomarkers:

• Low CSF Aβ42 1
• Positive PET amyloid imaging 1

Neurodegeneration Biomarkers:

• Elevated CSF tau (total tau and phosphorylated tau) 1
• Decreased FDG uptake on PET in temporoparietal cortex 1
• Disproportionate atrophy on structural MRI in medial, basal, and lateral temporal lobe and medial parietal cortex 1

If both amyloid and neurodegeneration biomarkers are present, the likelihood is high that dementia is due to Alzheimer disease; if both are absent, dementia is highly unlikely to be due to Alzheimer disease. 1

Management and Treatment

Nonpharmacologic Approaches (First-Line)

Patients may benefit from 3, 7:

• Cognitively engaging activities such as reading 3
• Physical exercise such as walking 3
• Socialization such as family gatherings 3
• Structured activities, caregiver education, and environmental modifications 5

Pharmacologic Approaches for Alzheimer Disease

For symptomatic relief in Alzheimer disease 3:

• Acetylcholinesterase inhibitor (such as donepezil) for mild to severe dementia 3
• Memantine (used alone or as add-on therapy) for moderate to severe dementia 3

Management of Behavioral and Psychological Symptoms

Behavioral and psychological symptoms of dementia (BPSD) occur in approximately 80% of patients 7. Nonpharmacologic strategies are first-line treatment, but psychotropic medications are often necessary when nonpharmacologic methods are not effective 7:

• SSRIs may help with behavioral symptoms, though they can worsen insomnia 5
• Antipsychotics may be considered when symptoms are distressing or causing dangerous behaviors, weighing risks and benefits 7

Disease-Specific Considerations

Currently, there is no specific disease-modifying treatment available for frontotemporal dementia, with treatment focusing on symptomatic management of behavioral symptoms 5.

Important Clinical Nuances and Pitfalls

Memory Is Not Always the Primary Deficit

Memory impairment is not always the primary deficit in dementia, and nonamnestic presentations can occur, particularly with onset before age 65. 2, 5 This includes language-predominant, visuospatial-predominant, or executive dysfunction-predominant presentations 2.

Psychiatric Symptoms Are Common

More than half of patients who develop dementia have depression or irritability symptoms before cognitive impairment becomes apparent 6, 5. However, when evaluating suspected dementia, primary psychiatric disorders should be actively excluded through rigorous application of DSM-5 criteria combined with expert clinical judgment 2. Consultation with a psychiatrist with expertise in frontotemporal dementia is recommended when primary psychiatric disorders are on the differential diagnosis 2.

Sharp Demarcations Are Difficult

Sharp demarcations between normal cognition and MCI, and between MCI and dementia, are difficult, and clinical judgment must be used to make these distinctions 1.

Progression Is Not Inevitable

Mild neurocognitive disorder is a disorder that may progress to dementia—importantly, it may not 8. The presence of neuropsychiatric symptoms is common among individuals with MCI and is an important risk factor for progression to dementia 8.