Major Neurocognitive Disorder (Dementia)

Etiology

Several conditions can cause MNDs, with Alzheimer dementia being the most common cause, accounting for about 70% of cases.[6] The DSM-5 criteria for MND further delineate 13 etiological subtypes that indicate the possible etiology of the disorder. These subtypes include Alzheimer disease, vascular disease, frontotemporal lobar degeneration, Lewy body disease, Parkinson disease, HIV infection, Huntington disease, prion disease, substance and or medication use, traumatic brain injury, another medical condition, multiple etiologies, and unspecified. A patient may have more than 1 etiology contributing to MND. For example, there may be a mixed picture of Alzheimer disease with vascular disease in the same patient. Other medical conditions that can lead to dementia include progressive supranuclear palsy, corticobasal syndrome, and, less commonly, multiple system atrophy. The etiology is further characterized by "possibly" vs. "probably," assigning the degree of certainty as to the cause of the MND. It often takes time to distinguish the etiology. It can be aided by many factors, including the results of imaging studies, lab studies, genetic markers, patient comorbidities, medical and family history, and clinical findings.[1] 

Epidemiology

Alzheimer disease is the most common cause of dementia, as it is responsible for 70 to 80% of all cases of dementia. It can occur sporadically or be familial.[7] Vascular dementia accounts for approximately 15% of all dementia cases. Its incidence increases with age and doubles every 5.3 years. Risk factors for vascular dementia include hypercholesteremia, diabetes mellitus, hypertension, and smoking.[8] Lewy body dementia accounts for approximately 5% of dementia cases. The epidemiological data may not be completely accurate because the diagnosis of Lewy boy dementia is often missed.[9] Parkinson disease dementia accounts for approximately 10% of cases of dementia.[9] Frontotemporal dementia is attributed to 25% of dementia cases in patients older than 65 years of age. It is, however, the second most common cause of dementia in patients younger than 65 years. There are, however, many limitations in the epidemiological studies of frontotemporal dementia, in part due to the inherent difficulty in identifying frontotemporal dementia.[10] Creutzfeldt-Jakob disease is rare and occurs in about 1 to 2 cases per million per year globally.[11] Mixed dementia is a condition in which patients have more than 1 type of dementia. In this condition, Alzheimer disease with vascular dementia is the most common coexistent dementia.[12] 

Pathophysiology

The pathophysiology of MND, or dementia, varies depending on the subtype. Most types, except vascular dementia, are caused by the accumulation of native proteins in the brain. Alzheimer disease is characterized by widespread atrophy of the cortex and deposition of amyloid plaques, and neurofibrillary tangles of hyperphosphorylated tau protein in neurons, which contribute to their degeneration.[7] Lewy body dementia and Parkinson disease dementia are characterized by the intracellular accumulation of Lewy bodies, which are insoluble aggregates of alpha-synuclein protein in the brain.[13] Frontotemporal dementia is characterized by various mutations leading to the deposition of ubiquitinated TDP-43 and hyperphosphorylated tau proteins in the frontal and temporal lobes, leading to dementia, early personality, behavioral changes, and aphasia depending on the subtype.[10] Huntington disease is caused by an autosomal dominant inherited gene mutation.

[14] Prion-related dementias are caused by misfolded prions, which are proteinaceous particles that are infectious in nature and self-spreading. Prion dementias include Creutzfeldt-Jakob disease and kuru, among other syndromes.[15] HIV infection is associated with the development of neurocognitive disorders, in part due to the activation of macrophages and toxic inflammation leading to neurodegeneration in the brain.[16] Alcohol consumption, particularly high doses, and prolonged use are associated with multiple cytotoxic processes within the brain.[17] Vascular dementia is caused by ischemic injury to the brain (eg, stroke), leading to permanent neuronal death.[18]

Histopathology

The pathological changes in the brain of patients with different types of dementia can be varied. However, there is often overlap and mixed presentations and findings. Neurodegeneration and vascular changes are seen in the brains of patients with vascular dementia. The findings can vary and are related to the underlying etiology of vascular compromise, including lacunar infarcts, hemorrhagic lesions, and microvascular disease.[19] There is considerable overlap of neuropathological findings between dementia with Lewy body and Parkinson disease, and some overlap with Alzheimer disease. Lewy body dementia and Parkinson disease are characterized by the presence of Lewy bodies throughout the neocortex, brainstem, and limbic regions of the brain. Lewy bodies are intracellular aggregates of proteins, predominantly composed of alpha-synuclein proteins, which can be highlighted by various stains depending on location within the brain.  There is also a loss of midbrain dopaminergic neurons and a loss of cholinergic neurons in ventral forebrain nuclei. Additionally, there are neuritic plaques made up of amyloid and neurofibrillary tangles, which can overlap findings in AD.[20] Alzheimer disease is characterized by neuritic plaques composed of extracellular amyloid beta protein deposition and neurofibrillary tangles composed of hyperphosphorylated tau proteins. It is also common to see signs of vascular ischemic damage and hippocampal sclerosis.[21][22] Frontotemporal dementia is characterized by atrophy in the frontal and or temporal lobes. There is neuronal loss, microvacuolation, and loss of myelin. Degeneration is found in the cortical and basal ganglia. Four pathological subtypes are named after the proteins that make up inclusions found in the brain tissue. FTLD-tau and FTLD-TDP are the most common. FTLD-FET is less common, and FTD-UPS is quite rare.[23] Cruetzfield Jakob disease often does not need an autopsy for diagnosis; however, it shows loss of neurons, spongiform degeneration (vacuoles in the intraneuronal space), or plaques positive for PrPSc.[24]

History and Physical

History must be obtained from the patient and their close friends, family members, or caregivers. Patients may present with symptoms of changes in behavior, getting lost in familiar neighborhoods, memory loss, mood changes, aggression, social withdrawal, self-neglect, cognitive difficulty, personality changes, difficulty performing tasks, forgetfulness, difficulty in communication, loss of independence, etc. A detailed history should include past medical, family, medication, and substance use history and defining observed symptoms of cognitive decline. Often, patients report different awareness of the deficits than caregivers or companions. In addition to further characterization of the cognitive changes, it is important to evaluate their current functional abilities and any changes in their ability to perform daily tasks. Evaluating any safety concerns arising from the cognitive changes is also vitally important. For example, is the patient still driving and doing so safely? Have there been any episodes of wandering or getting lost? Could they get out safely if there was a fire in the house? Can they still use the telephone? Are they vulnerable to financial or physical abuse? Are there firearms in the home to which they have access? 

In addition to symptoms of dementia, the following atypical symptoms may be seen in the following conditions:

• In patients with Lewy body dementia, symptoms of well-formed visual hallucinations, REM sleep behavior disorder, typical parkinsonian symptoms, and fluctuating cognition, attention, and alertness.[20] 
• In patients with frontotemporal dementia, behavior changes, including disinhibition and apathy, and speech difficulties may be seen.[25]
• In patients with Creutzfeld-Jakob disease, myoclonus symptoms, visual changes, ataxia, and memory and behavior changes are seen.[26] 
• In patients with Huntington disease, symptoms of chorea, irritability, and depression can be present.[14]
• In patients with vascular dementia, deficits can occur in stepwise declines.[27] 
• In patients with Parkinson disease dementia, symptoms of parkinsonism characterized by bradykinesia, resting tremor, and muscle rigidity are found. In addition, visual hallucinations and delusions may also be seen, especially in the late stages.[20] 

Patients with atypical parkinsonian syndromes also bear mentioning. Multiple system atrophy, progressive supranuclear palsy, and corticobasal syndrome have symptoms of parkinsonism in addition to other characteristic findings. Multiple system atrophy has symptoms of autonomic failure and cerebellar ataxia. Progressive supranuclear palsy has symptoms of frequent falls (often backward) and vertical supranuclear gaze palsy. Corticobasal syndrome has progressive asymmetric muscle rigidity and alien limb phenomenon.[28] The physical exam should be comprehensive, including a complete neurological exam including gait analysis. 

Evaluation

The definitive diagnosis of the type of dementia can only be made at autopsy. A probable diagnosis can often be made using clinical history predominantly, sometimes aided by brain imaging and additional laboratory evaluation. Excluding treatable causes of cognitive impairment is also important in the initial evaluation. All domains of cognition must be assessed. There are multiple cognitive evaluation tools available for use in a clinical setting, including the Mini-mental status examination, Montreal Cognitive Assessment, Saint Louis University Mental Status, Addenbrooke's Cognitive Examination–Revised, the modified mini-mental state examination, Mini-Cog, and Rowland Universal Dementia Assessment Scale.  See Table. Pain Assessment in Advanced Dementia Scale.

Each tool has different advantages; for example, the Montreal cognitive assessment takes approximately 10 minutes and is better suited for detecting mild cognitive impairment besides MND. In contrast, the Mini-Cog takes approximately 3 minutes to administer and is predominantly used to screen for MND. The Rowland Universal Dementia Assessment Scale is often used for cross-cultural evaluations and can be administered with an interpreter. None of these cognitive evaluations alone can diagnose MND, as a decline in function of daily tasks is also needed to meet the diagnostic criteria. These studies can be repeated over time to document the progression of decline. They can give an idea of the severity of the deficit along with specific cognitive domains that are affected. Specialized, more in-depth neuropsychological testing can provide further diagnostic information and help differentiate subtle differences or hard-to-diagnose cases. Laboratory tests to check in all patients during the evaluation of dementia include complete blood count, urinalysis, metabolic panel, Vitamin B12, folic acid, thyroid function tests, and serological tests for syphilis and HIV. Under certain circumstances, checking erythrocyte sedimentation rate, lumbar puncture, heavy metal screen, ceruloplasmin levels, Lyme disease titer, or serum protein electrophoresis may be appropriate. 

Brain imaging is sometimes ordered, particularly if the age of onset is relatively early, atypical or rapidly progressing symptoms are present, or there is diagnostic uncertainty. A brain MRI without contrast is often the initial test ordered. It is valuable for evaluating signs of vascular or ischemic disease and localized regions or global atrophy that may be seen. A DaTscan uses a radiotracer to highlight dopamine transporter proteins in a SPECT scan on the presynaptic dopaminergic neurons. This scan can aid in differentiating pathologies that involve loss of the striatal dopaminergic pathway, including Parkinson disease, multiple system atrophy, progressive nuclear palsy, cortical-basal degeneration, and Lewy body dementia from other syndromes.[29] Often reserved for academic settings, functional brain imaging with PET, SPECT, and fMRI can help in the early diagnosis and monitoring of patients with dementia, especially AD. These can also help differentiate the etiology of dementia. These are expensive, and routine use in clinical practice is not indicated.[30] There are new CSF and blood tests under research to help identify Alzheimer disease and evaluate concentrations of amyloid and phosphorylated tau proteins as well as markers of neurodegeneration, including neurofilament light chain and glial fibrillar acidic proteins. These tests are not yet ready for regular clinical use.[31]

Treatment / Management

FDA-approved medications to improve cognitive function include cholinesterase inhibitors and memantine. Cholinesterase inhibitors include donepezil, galantamine, and rivastigmine. Cholinesterase inhibitors prevent the breakdown of acetylcholine and aim to slow or delay the worsening of symptoms. Memantine is an NMDA antagonist and decreases the activity of glutamine. Donepezil is approved for all stages of Alzheimer disease, rivastigmine is approved for all stages of Alzheimer disease in its patch form, and mild to moderate stages with oral formulations. Galantamine is approved for mild to moderate stages and memantine for moderate to severe stages.[32] Acetylcholinesterase inhibitors lead to a variable response among patients, with not all patients showing benefit. There are possible contraindications to their use and significant side effects, including the potential for cardiovascular complications, peptic ulcer disease, and weight loss. Memantine may have neuroprotective benefits as it serves as an uncompetitive NMDA receptor antagonist and can prevent neurotoxic and excessive calcium influx to the neuron.[33] The benefits seen with the use of both acetylcholinesterase inhibitors and memantine are often modest, and many patients and providers choose to forgo pharmacologic treatment. 

Aducanumab is a recombinant monoclonal antibody directed against amyloid beta that was recently approved by the FDA for the treatment of mild Alzheimer disease. Its approval remains highly controversial. The drug is costly and does not have clear, proven clinical benefits. It was approved based on positive clinical results seen in only 1 of the 2 phase III trials and aducanumab's effect on a surrogate endpoint (reducing amyloid beta plaques in the brain), which has not been proven clinically significant.[34] Lifestyle modifications to optimize cognitive function include optimizing sleep, eating an anti-inflammatory diet, adequate exercise, treating hearing or vision loss, minimizing stress, and maintaining normal blood sugar, cholesterol, and blood pressure levels.[35] Behavioral symptoms include irritability, anxiety, and depression. Antidepressants and sometimes antipsychotics can help with these symptoms. In addition, non-drug approaches like supportive care, memory training, physical exercise programs, and mental and social stimulation must be employed in symptom control. Patients and their families should be counseled about the disease and its consequences. They should be provided with all the necessary information about what to expect and how to react. Patients and their families should also be encouraged to seek social service consultations and to register with support groups and societies. Coaching caregivers on skills such as redirection and reassurance as opposed to repeated correction of patients confused due to dementia can avoid or de-escalate possible behavioral symptoms. Driving restrictions may have to be imposed.

Differential Diagnosis

The differential diagnosis for major neurocognitive disorder (dementia) include the following:

• Delirium 
• Depression 
• Drug use
• Normal age-associated memory changes 
• Mild cognitive impairment 
• Stress
• Structural brain abnormalities like subdural hematoma, brain tumor, and normal pressure hydrocephalus
• Infections like HIV and neurosyphilis
• Thiamine deficiency
• Vitamin B12 deficiency
• Folic acid deficiency 
• Thyroid disorders
• Metabolic abnormalities and derangements
• Medication-induced
• Vitamin E deficiency

Prognosis

The prognosis of dementia is poor. Dementia is often a progressive condition with no cure or treatment. The 1-year mortality rate was 30 to 40%, while the 5-year mortality rate was 60 to 65%. Men had a higher risk than women. Mortality rates among admitted patients with dementia were higher than those with cardiovascular diseases.[36]

Complications

Dementia can affect many body systems and can lead to the following complications:

• Inadequate nutrition
• Pneumonia
• Inability to perform self-care tasks
• Personal safety challenges
• Fractures due to falls
• Hallucinations and delusions
• Apathy
• Agitation
• Dysphagia
• Death
• Depression
• Incontinence
• Personality changes
• Infections[37]