Major Neurocognitive Disorders

Major neurocognitive disorders (NCDs), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. There are several distinct etiologies for major NCDs. While there are known risk factors and measures to prevent major NCDs, there are no effective curative treatments.

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  • The term “major neurocognitive disorders (NCDs)” describes a group of disorders characterized by progressive cognitive impairments.
  • Also known as dementia
  • To be classified as an NCD, there must be a clear decline from previous levels of functioning and cognitive baseline in a person.


  • About 20% of people above 65 years of age meet the criteria for major NCD. 
  • About 70% of these patients have Alzheimer disease (most common cause of major NCD).
  • Prevalence increases with age to a rate of ≥ 20% for patients over the age of 85 years.
  • Serious economic and social impact, as these individuals often require a caregiver for the rest of their lives


Most common:

  • Alzheimer disease
  • Vascular dementia
  • Lewy body dementia
  • Parkinson’s disease dementia
  • Frontotemporal dementia
  • Metabolic abnormalities (hypothyroidism, uremia) 
  • Nutritional deficiencies (vitamin B12/folate deficiency)
  • Dementia secondary to depression 

Less common:

  • Creutzfeldt-Jakob disease
  • Wernicke-Korsakoff syndrome
  • Huntington disease
  • HIV dementia 

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Pathophysiology of the most common causes of the major NCDs are shortly described below.

Alzheimer disease

  • Accounts for 60%–70% of dementia cases
  • Characterized by:
    • Loss of neurons in cortex and subcortex → atrophy of primarily the temporal and parietal lobe
    • Accumulation of beta-amyloid plaques, tau protein, and potentially Lewy bodies inside neurons
Alzheimer’s disease on mri

Alzheimer disease:
T1-weighted MRI image showing bilateral hippocampal atrophy typical for Alzheimer disease

Image: “Magnetic resonance imaging: T1-weighted coronal image showing bilateral hippocampal atrophy in Alzheimer’s disease” by Kuruvilla T, Zheng R, Soden B, Greef S, Lyburn I. License: CC BY 3.0

Vascular dementia

  • Primary cause of vascular dementia is cerebral vascular disease.
  • Risk factors: same as those for cardiovascular disease 
  • Reduction in cerebral perfusion → disruption of brain connectivity, cerebral atrophy

Dementia with Lewy bodies

  • Lewy bodies are thought to be responsible for impaired mental functions related to thinking, movement, behavior, and mood in dementia with Lewy bodies.
    • Abnormal aggregation of protein (α-synuclein) within nerve cells is the chief component of Lewy bodies. 
    • Found abundantly in brain cells of people suffering from dementia with Lewy bodies and Parkinson’s disease dementia (less commonly in Alzheimer disease)
  • Presence of Lewy bodies alters the level of neurotransmitters and neuromodulators in the brain, principally dopamine. 

Parkinson’s disease dementia

  • Loss of pigmented dopaminergic neurons in the substantia nigra (pars compacta) 
  • Presence of Lewy bodies
  • Leads to destruction of brain cells and depletion of dopamine (hormone that controls muscle coordination) in the basal ganglia
Photomicrograph of a lewy body

Photomicrograph of a Lewy body (arrowhead) in the cytoplasm of a neuron in the substantia nigra from a person with Parkinson’s disease:
The tissue section was stained with hematoxylin and eosin (purple and pink, respectively). The brown material is neuromelanin, which occurs naturally in neurons of the human substantia nigra.

Image: “Lewy body in the substantia nigra from a person with Parkinson’s disease” by Tulemo. License: CC BY-SA 4.0

Frontotemporal dementia

  • Different types of dementia affecting the frontal and temporal lobes
  • Damage to neurons → shrinkage of the frontal and temporal lobes of the brain
  • Assumed to have stronger genetic component than other types of dementia
  • Mostly affecting people aged 50–60, but can also manifest much earlier or later 

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Clinical Presentation

General features

Significant decline in cognition in the following domains: 

  • Attention
  • Executive function
  • Learning/memory
  • Language
  • Perception
  • Social interaction

Symptoms are not explained by other medical, psychiatric conditions (depression, delirium).

Specific subgroups of dementia

Table: Differences in clinical features among the various causes of major NCDs
Feature Alzheimer disease Vascular dementia Frontotemporal dementia Dementia with Lewy bodies
Onset of Symptoms Insidious Stepwise progression Pre-senile onset Insidious
Cognitive symptoms Decline in memory and executive function Decline in executive function Decline in executive function
  • Decline in executive and visuospatial function
  • Hallucinations
Motor symptoms Usually rare Depending on location of lesion Parkinsonian symptoms in certain cases Parkinsonian symptoms follow cognitive symptoms


History and exam

  • Determine onset and development of symptoms.
  • Involve collateral information from caregiver, if possible.
  • Mental status exam: 
    • Cognition must be tested separately using screening tests. 
      • Examples: Mini-Cog, mini-mental state examination (MMSE), and Montreal Cognitive Assessment (MoCA)
      • No one test is superior clinically to another.
    • It is recommended to repeat the screening tests to detect progression of the cognitive decline.
    • Be wary of symptoms of depression, anxiety, or paranoia, which can present concurrently with cognitive impairment!
Table: Characteristics of important screening tests for major NCDs
Screening test Mini-Cog MMSE MoCA
Time to administer test < 5 minutes 6–10 minutes About 10 minutes
Number of questions 2 20 18
Cognitive dimensions tested
  • Memory
  • Visuospatial function
  • Executive functions
  • Orientation
  • Memory
  • Language
  • Attention
  • Visuospatial function
  • Orientation
  • Memory
  • Language
  • Attention
  • Visuospatial function

Further workup tests

The following are mostly used to differentiate or rule out treatable medical or neurologic conditions that cause a decline in cognition: 

  • Basic lab tests: 
    • CBC
    • Electrolytes 
    • Thyroid-stimulating hormone (TSH) 
    • Vitamin B12 and folate levels
    • Urinalysis
  • Ancillary labs:
    • HIV antibodies (→ HIV-associated dementia)
    • Rapid plasma reagin (→ syphilis)
    • Serum copper, ceruloplasmin levels (→ Wilson disease)
    • CSF analysis: 
      • Beta-amyloid 
      • Total tau
      • Phosphorylated-tau (p-tau)
  • Imaging of the head:
    • Mostly to rule out tumors and vascular disease 
    • CT
    • MRI
    • PET 
  • Neuropsychological tests: 
    • Assess ability to speak and work with numbers, memory, and problem-solving skills.
    • Can distinguish symptoms from various etiologies of major NCDs


General approach

  • Identify and treat reversible causes of major NCD early.
  • For nonreversible cases, management techniques focus on preserving quality of life by prevention as well as treatment of symptoms. 
  • To date, there are no treatments to completely cure major NCDs. 


  • Control of blood pressure, cholesterol levels, and blood glucose level
  • Regular physical activity and healthy diet
  • Smoking cessation 
  • Cognitive exercises 


  • Treatments for Alzheimer disease dementia:
    • Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine)
    • Increase the amount of available neurotransmitters and thus transmission of signals.
    • Long-term use modestly stabilizes cognitive decline for 6–12 months longer than no treatment. 
    • Side effects:
      • Nausea
      • Diarrhea
      • Insomnia
      • Muscle cramps
    • Also has shown benefits for managing major NCDs such as dementia with Lewy bodies and Parkinson’s disease dimentia
  • Drugs to avoid: 
    • Antipsychotics (haloperidol and quetiapine):
      • Lead to altered consciousness, confusion, and hallucinations
      • Use only in acute, severe cases of agitation 
    • Benzodiazepines: increase fall risk 

Caregiver support

  • Educating and providing support for caregivers is an essential part of the treatment plan. 
  • Long-term outcome of those with major NCDs has been shown to be dependent on the wellness of the caregivers.

Complications and Prognosis


  • Frequent hospitalizations due to: 
    • Frequent falls, fractures 
    • Behavioral disturbances with increased agitation and personality changes 
    • Inability to take care of oneself 
  • Death: 
    • Often caused by acute illnesses due to increased frailty
    • 2 leading causes: pneumonia and ischemic heart disease 


  • Prognosis for major NCDs is very poor.
  • 5-year mortality: estimated at 60% 
  • Earlier onset or family history of dementia is linked with more rapid course of the disease.

Differential Diagnosis

  • Delirium: an acute change in mental status characterized by impairments in attention, cognition, and arousal. Similar to dementia, delirium is highly prevalent among the elderly population. While delirium is always of acute onset, dementia progresses gradually, with worsening of the symptoms. Patients with dementia are consciously alert and pay attention to the current happenings, whereas patients with delirium have altered consciousness levels. 
  • Depression: characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of at least 2 weeks. Depression in elderly patients can manifest as “pseudodementia,” where the patient presents with cognitive decline much like that seen in NCDs. Those with pseudodementia will have more prominent depressive mood symptoms, often a prior history of depression, and better insight into their condition than those with dementia. 
  • Normal aging: minor memory problems may occur as part of normal aging. The associated minor cognitive decline is called benign senescent forgetfulness. The amount of memory impairment is difficult to quantify in normal aging; however, it is clearly distinguished from major NCDs due to the patient having intact activities of daily living as well as no issues with orientation. 


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