Etiology

A thorough history and physical exam, supported by appropriate investigations, are of utmost importance in differentiating dementia from mild cognitive impairment and normal aging. Prompt and thorough cognitive assessment quantifies the memory deficits and ensures appropriate diagnosis.[8][9]

It is important to consider the etiology of dementia syndrome because an estimated 11% to 14% of cases are caused by potentially reversible conditions.[6][7]

Furthermore, medications such as cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine are thought to slow the progression of Alzheimer disease. [ Cochrane Clinical Answers logo ]

Mild cognitive impairment (MCI)

MCI is defined as a condition characterized by newly acquired cognitive decline to an extent that is beyond that expected for age or educational background, yet not causing significant functional impairment. MCI is conceptualized as a transitional state between the cognitive changes of normal aging and very early dementia.

Once the diagnosis of MCI is established, the next task is to identify the clinical subtype. There are two subtypes of MCI, amnestic and nonamnestic.[10] Patients with memory impairment (taking into account age and education) have amnestic MCI. If memory is relatively spared, but the person has impairment in other nonmemory cognitive domains, such as language, executive function, or visuospatial skills, this constitutes nonamnestic MCI. 

Patients with amnestic MCI typically progress to Alzheimer disease at a rate of 10% to 15% a year. These progression rates far exceed the population incidence figures for Alzheimer disease of 1% to 2% a year.[11]

Degenerative and vascular

The majority of cases of dementia have degenerative and vascular causes.[5] More than one cause may be contributing to the dementia syndrome.

  • Degenerative causes include Alzheimer disease (the most common cause of dementia accounting for an estimated 60% of cases), Lewy body disease, Parkinson disease, frontotemporal atrophy with and without Pick bodies, Huntington disease, progressive supranuclear palsy, and spinocerebellar degeneration.[12] More recently, the disease entity limbic-predominant age-related TDP-43 encephalopathy (LATE) has been described.[13] LATE neuropathologic change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. It is associated with an amnestic dementia syndrome that mimicked Alzheimer-type dementia in retrospective autopsy studies, and is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on the relatively restricted neuroanatomical distribution of TDP-43 proteinopathy and its epidemiology (LATE generally affects older subjects).[13]

  • Vascular causes account for 5% to 20% of dementia cases.[5][14] Although the term multi-infarct dementia was very popular in the past, this term is misleading. Multi-infarcts are just one of the many reasons for dementia due to vascular causes. The currently accepted term is vascular dementia, which includes dementia due to multiple infarcts, a strategic single infarct, hemorrhage, hypoperfusion, delayed effects of irradiation, vasculitic disorders involving the central nervous system, cardiac disorders, and Binswanger disease.[15][16][17] Binswanger disease, also called subcortical vascular dementia, is caused by widespread, microscopic areas of damage to the deep layers of white matter in the brain. It is a pathologic diagnosis and a rare cause of vascular dementia.

Psychiatric and neurologic

Psychiatric causes of memory problems include delirium, depression, and amnestic syndromes.

Dementia and depression may coexist, and depression increases the 5-year risk of institutionalization and death in people with dementia.[18] Over 25% of patients with neurodegenerative disorders receive a prior psychiatric diagnosis, most frequently depression. Patients with behavioral variant frontotemporal dementia are at highest risk for misdiagnosis.[19]

Neurologic causes of dementia include normal-pressure hydrocephalus (NPH).

Neoplastic

Neoplastic causes include metastatic lesions of the brain, primary brain tumors, primary meningeal tumors, and carcinomatosis.

Endocrinologic, metabolic, and nutritional deficiency

Related causes include vitamin B12 or folate deficiency, Cushing disease, hypopituitarism, parathyroid disease, porphyria, thyroid disease (hypo- or hyperthyroid state), uremia, and Wilson disease.

Traumatic

Causes include subdural hematoma and traumatic brain injury hypoxemic anoxia. Patients with head trauma may develop memory problems, although the link between head injury and dementia is controversial.[20][21][22]

After experimental brain trauma, the long-term accumulation of amyloid beta peptide suggests that neurodegeneration is influenced by apolipoprotein E epsilon 4. After human brain injury, both amyloid beta peptide deposition and tau pathology (in which tau protein, a microtubule-associated protein, accumulates as neurofibrillary tangles and dystrophic neurites) are seen, even in younger patients. Amyloid beta peptide levels in the cerebrospinal fluid and the overproduction of beta amyloid precursor protein in humans after traumatic brain injury are increased. Repeated head trauma in humans accelerates the amyloid beta peptide accumulation and cognitive impairment. Retrospective autopsy data support clinical studies suggesting that severe traumatic brain injury with long-lasting morphologic residuals are a risk factor for the development of dementia.[20]

Infectious

Causes include Lyme disease, neurosyphilis, and tuberculosis meningitis. There has been an increase in cases of syphilis in low- and middle-income countries and in certain populations in developed countries in recent years, but the diagnosis of neurosyphilis tends to be overlooked because of its rarity.[23]

Creutzfeldt-Jakob disease (CJD) is a rare but fatal neurodegenerative disease caused by an infectious protein called prion and is characterized by spongiform changes, neuronal loss, reactive astrocytic proliferation, and accumulation of pathologic cellular protein.[24] It occurs in three general forms: sporadic or spontaneous, genetic or familial, and acquired form, including a variant form of CJD. It is a rapidly progressive dementia resulting in death, usually from respiratory infection.[24]

Inflammatory

Causes include demyelinating diseases, lupus erythematosus, sarcoidosis, Sjogren syndrome, and limbic encephalitis.

Iatrogenic

Medication-related causes include antihistamines and anticholinergic medications.[25][26][27] There is some evidence that androgen deprivation therapy may be associated with an increased risk of dementia, but this remains controversial and further investigation is required.[28]

Toxic

Alcohol; heavy metals such as arsenic, lead, and mercury; histotoxic anoxia due to carbon monoxide; and cyanide are possible causes.

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