Introduction to Dementia

Dementia is a progressive neurocognitive decline of sufficient magnitude to interfere with normal social or occupational functions, or with usual daily activities. It is a broad diagnostic category that includes Alzheimer's disease, Lewy Body dementia, frontotemporal dementia, vascular dementia, Parkinson's disease, and Creutzfeldt–Jakob disease (among many others). It also includes rapidly progressive dementias that may be fully reversible if the etiology is correctly identified.

With normal aging, semantic memory and visuospatial functioning is generally preserved. Decline in problem-solving, processing speed, and minor delays in word-finding can be common. Retrieval-type memory deficits can also occur.

About 35%-40% of dementia cases are attributable to nine modifiable factors across the lifespan.[1] These factors include: education, midlife hypertension, midlife obesity, hearing loss, late-life depression (note: depression likely has a bidirectional relationship with dementia risk, as it can be both a risk factor for dementia and a prodrome of dementia), diabetes, physical inactivity, smoking, and social isolation.[2]

More recently, the 2020 Lancet Commission on Dementia Prevention, Intervention and Care updated the risk factors to now include 12 potentially modifiable risk factors across the lifespan that can contribute to dementia: early life (education), midlife (hypertension, obesity, hearing loss, traumatic brain injury, and alcohol misuse) and later life (smoking, depression, physical inactivity, social isolation, diabetes, and air pollution).[3] There is some debate as to how many of these cases with modifiable risk factors can truly be prevented even with risk factor modification.[4]

Dietary supplementation to prevent dementia has been a source of controversy due to a lack of convincing evidence from current studies, low quality studies, and multiple confounders in dietary research.[5] Vitamins B and E, polyunsaturated fatty acids, and multivitamins are not recommended for risk reduction of dementia.[6]

The World Health Organization (WHO) Dementia Prevention Guidelines

The World Health Organization (WHO) Dementia Prevention Guidelines recommends the following to reduce the risk of dementia:[7]
  1. Physical exercise (there is some conflicting data[8])
  2. Lose excess weight in midlife
  3. Adhere to healthy diet (a Mediterranean-style diet may reduce dementia risk)
  4. Cognitive training can be tried for adults with normal cognition or mild impairment (but the quality of evidence to support this is low)
  5. Social participation and support are important throughout life (but limited evidence to support)
  6. Hypertension, diabetes, and depression should be managed according to existing guidelines (but it is not clear whether doing so will specifically lower dementia risk)

When seeing a patient with a non-rapidly progressive dementia (otherwise, see the rapidly progressive dementia approach below), it is good to have a systematic approach. The following is one approach:[9]

  1. Rule out delirium. Is there an acute onset and fluctuating course + inattention + disorganized thinking? Is there altered level of consciousness?
    • Urinary Tract Infections (UTIs) are especially common in the elderly and frequent culprits of delirium! Don't forget that a negative urine culture does not always mean there is no UTI, especially if the patient is symptomatic.[10]
  2. Rule out depression (“pseudodementia”). Consider atypical presentations: anxiety, irritability, unexplained physical complaints, worsening cognition. Once the depression is treated, the dementia symptoms go away!
  3. Rule out any substance use disorders
  4. Rule out any reversible causes
    • Order CBC (anemia), TSH (hypothyroidism), creatinine, electrolytes (hyponatremia), calcium (hypercalcemia), glucose (hyperglycemia), ferritin/iron, and vitamin B12 (vitamin B12 deficiency)
    • Creatinine (to assess renal function and ability to clear medications)
    • Consider neuroimaging such as CT or MRI
    • Consider rapid plasma reagin (RPR), LFTs
    • Is there the use of any anticholinergic medications (and anticholinergic toxicity?)
  5. Is it dementia, mild cognitive impairment (MCI), or normal aging?
    • Dementia: objective findings of cognitive loss with impairment of ADLs
    • Mild Cognitive Impairment: objective findings of cognitive loss without impairment of ADLs
    • Normal cognitive aging: no objective findings of cognitive loss

Common Dementia Subtypes and Presentation

Subtype Percent of Dementia Cases Typical presentation
Alzheimer's Disease (AD) ~50% Initial short-term memory loss
Vascular Dementia* ~25% Vascular risk factors; neuroimaging evidence of cerebrovascular involvement
Lewy Body Dementia (LBD) 15% Bradykinesia or features of parkinsonism, fluctuating cognition, visual hallucinations
Frontotemporal Dementia (FTD) 3% Younger age, behavioural symptoms, or language impairment
Parkinsons's Disease Dementia (PDD) 0.5%[11] (most cases of Parkinson's will progress to dementia) Dementia occurring > 1 year after onset of Parkinson disease motor symptoms

Rare Dementia Subtypes and Presentation

Subtype Prevalence Typical presentation
Corticobasal Degeneration (CBD) 5 per 100,000 [12] Progressive asymmetric movement disorder with symptoms initially affecting one limb, plus cognitive or behavioural disturbances.
Creutzfeldt-Jakob Disease (CJD) 1 per 1 million Rapid, progressive mental deterioration with myoclonus and abnormal movements. Survival rate is less than 1 year.
Primary Progressive Aphasia (PPA) 2.7 to 15 per 100,000[13] Begins with gradual, subtle language deficits that progresses to a nearly complete inability to speak.
Progressive Supranuclear Palsy (PSP) 5.8 to 6.5 per 100,000[14] Characterized by early postural instability, leading to falls, and a characteristic vertical supranuclear-gaze palsy on physical exam.

Dementia is often due to more than one pathology. Some studies have shown that in a general population, 40% of patients have a combination of Alzheimer's Disease (AD) and vascular dementia, while only 30% had pure Alzheimer's and 12% had pure vascular dementia (VaD). About 12% had Alzheimer's combined with Parkinsons's Disease Dementia (PDD) (PD) or Lewy Body Dementia (LBD).[15]

Behavioural and Psychological Symptoms of Dementia (BPSD) will develop in more than 90% of individuals diagnosed with dementia. Symptoms include delusions, hallucinations, aggression, screaming, restlessness, wandering, depression, and anxiety.

For older patients with cognitive symptoms, neuroimaging with CT is recommended if the following criteria is present:[16]

  • Age less than 60 years
  • Rapid (e.g., 1 or 2 months) unexplained decline in cognition or function
  • “Short” duration of dementia (less than 2 years)
  • Recent and signicant head trauma
  • Unexplained neurological symptoms (e.g. new onset of severe headache or seizures)
  • History of cancer (especially in sites and types that metastasize to the brain)
  • Use of anticoagulants (i.e. - history of atrial fibrillation) or history of bleeding disorder
  • History of urinary incontinence and gait disorder early in the course of dementia (as may be found in normal pressure hydrocephalus)
  • Any new localizing sign (e.g., hemiparesis or a Babinski reflex)
  • Unusual or atypical cognitive symptoms or presentation (e.g. progressive aphasia)
  • Gait disturbance

Rapidly Progressive Dementias (RPDs) are dementias that progress quickly – over the course of weeks to months (in rarer cases, may be over a period of 1-2 years).[17] Treatment of an RPD is dependent on the etiology of the dementia, some of which are fully treatable. This makes early recognition critical. Broadly, RPDs can be broken down into different etiologies:

  1. Prion disease (e.g. - Creutzfeldt-Jakob Disease (CJD))
  2. Neurodegenerative diseases (e.g. - early onset Alzheimer's Disease (AD))
  3. Autoimmune
  4. Infectious
  5. Psychiatric
  6. Neoplastic
  7. Toxic-Metabolic
  8. Vascular
  9. Leukoencephalopathies (e.g. - Multiple Sclerosis (MS), Progressive Multifocal Leukoencephalopathy)

Mnemonic

Evaluating for RPDs requires a detailed and systematic approach, and a mnemonic can be useful to do this. The mnemonic VITAMINS can be used to remember the

  • V - Vascular
  • I - Infectious
  • T - Toxic-Metabolic
  • A - Autoimmune
  • M - Metastasis/Neoplastic
  • I - Iatrogenic
  • N - Neurodegenerative
  • S - Systemic/Seizures

RPDs: Vascular

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Multi-infarct VaD A/S >50 years, risk factors for vascular disease Stepwise cognitive decline, with localizing motor, visual, or sensory signs Multiple regions of T2/FLAIR hyper in vascular territories Nondiagnostic - Secondary prophylaxis, treatment of risk factors, AChI
Strategic infarct dementia A >50 years, risk factors for vascular disease Sudden onset of cognitive impairment, memory loss Hippocampal, thalamic, angular gyrus, PCA/ACA territory infarct(s) Nondiagnostic - Secondary prophylaxis, treatment of risk factors, IV high- dose corticosteroids
Inflammatory CAA S >40 years, M = F Subacute cognitive decline, headache, seizures Microbleeds on T2, large/ confluent hyper T2 lesions (hypo on T1) - Homozygous APOE e4 genotype; biopsy for confirmation -
Primary CNS angiitis A Peaks at ~50 years, M = F Cognitive decline, multifocal neurologic symptoms Multiple grey or white matter T2-hyper Might show pleocytosis or elevated protein CNS angiogram or brain and meningeal biopsy IV high-dose corticosteroids; immunosuppression
Cerebral venous sinus thrombosis (CVST) A/S Adults, F > M, pregnancy, hypercoagulable states Cognitive decline, confusion, focal neurologic signs, headache Venous clot; T2-hyper in adjacent GM and WM; possible restricted diffusion or hemorrhage Normal MRV, hypercoagulable tests Anticoagulation

RPDs: Infectious

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Neurosyphilis S Consider risk factors Cognitive decline, psychosis, depression, pupillary abnormalities Nonspecific atrophy, may be normal CSF VDRL Serum EIA/RPR Crystalline IV penicillin G for 10–14 dayse3
Whipple disease S Adults; rare in older adults Dementia, psychiatric symptoms, movement disorder, ophthalmoplegia, myoclonus, GI disturbance Normal vs FLAIR hyper in MTL, midbrain, diencephalon (+/- CE) Tropheryma whippelii PCR Jejunal biopsy (PAS + staining or PCR) Ceftriaxone 2 g/d x 2 weeks, then co- trimoxazole (>1 year)
Lyme disease S Any age; prevalence variable in different regions Dementia, cranial neuropathy, meningitis, psychosis, polyradiculopathy; neurologic manifestations are late Normal in most cases Lymphocytic pleocytosis; intrathecal production of Abs Serology Ceftriaxone 2 g/d x 14 days
HIV dementia A/S Seroconversion, older HIV-positive adults, low CD4 Psychomotor slowing, executive dysfunction, depression, movement disorders Cortical atrophy; nonspecific white matter changes Increased protein, mild pleocytosis HIV serology; serum and CSF viral loads CNS penetrating HAART
Herpetic meningoencephalitis A Any age Altered level of consciousness, focal deficits, seizures, behavioral changes; fever Medial temporal lobe hyper on FLAIR, asymmetric; later hemorrhagic necrosie6 Lymphocytic pleocytosis, [RBC, HSV-1 PCR1 EEG: focal abnormalities, PLEDs IV acyclovir for 14–21 days (start early if suspected)

RPDs: Toxic-Metabolic

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Wernicke-Korsakoff Syndrome A Risk factors: alcoholism, malnutrition Cognitive impairment, eye movement abnormalities, ataxia T2 hyper in medial thalamus and mammillary bodiese7 Nondiagnostic - Thiamine
Extrapontine myelinolysis A Rapid correction of electrolyte disturbance (e.g., hyponatremia) May take few days to develop symptoms; encephalopathy, movement disorders, para/quadriparesis Hyper T2 lesions (CE) in pons, cerebellum, basal ganglia, thalamus; may take days to appeare8 Nondiagnostic - Symptomatic
Vitamin B12 deficiency S Older adults, pernicious anemia, veganism, fad diets Cognitive impairment (infrequent, but treatable), sensory ataxia, paresthesias Nondiagnostic Nondiagnostic Vitamin B12, MMA, homocysteine Vitamin B12
Acquired hepatocerebral degeneration, hepatic encephalopathy S Cirrhosis (portosystemic shunting) Apathy, inattention, parkinsonism, cranial dyskinesia Pallidal T1 hyper, T2 normal Nondiagnostic Ammonia level Treatment of liver disease, but might be irreversible; liver transplant
Acute intermittent porphyria A/S 20s–30s; F > M Abdominal pain, autonomic dysfunction, behavioral changes, altered consciousness Normal Nondiagnostic Elevated PBG/ALA in urine Carbohydrates, intravenous haem arginate; avoid certain medications and metabolic disturbances

RPDs: Autoimmune

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
anti-NMDAR encephalitis A/S Median 19 years, F > M Flu-like prodrome, prominent psychiatric features (psychosis), hyperkinesias, autonomic instability Normal in 45%. T2 hyper in cerebral/ cerebellar cortex with meningeal CE Lymphocytic pleocytosis, OCB frequent Screening for tumor (mostly ovarian teratoma) See main article
Encephalopathy with VGKC antibodies (LGI1 antigen) S Median 60 years Limbic encephalitis, hyponatremia, seizures, myoclonus, ataxia, unilateral brachial-facial spasms MTL hyper on FLAIR in 85%; might be normal Normal/elevated protein, OCB infrequent <20% with tumors (SCLC, thymoma) EEG slowing See main article
Paraneoplastic Encephalitis and Syndromes S Any age (depends on antibody) Neuropsychiatric symptoms (anxiety, hallucinations), seizures, cognitive decline, headache, tremor, subacute onset, fluctuating course MTL hyper on T2/ FLAIR; might be normal Lymphocytic pleocytosis, normal/elevated protein +/- OCB Most frequent Abs: anti-CV2/CRMP5, Hu, Ma2 (10% seronegative) EEG slowing See main article
Acute demyelinating encephalomyelitis A More frequent in children Flu-like prodrome, post vaccination/viral infection; encephalopathy with multifocal neurologic signs Multifocal T2/FLAIR hyper, sometimes with CE Mild pleocytosis, protein <100 mg/ dL - IV corticosteroids (or PE, immunoglobulin)

RPDs: Metastasis/Neoplasia

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Primary CNS lymphoma S Most 50–70 years Neuropsychiatric symptoms, focal neurologic deficits, seizures Focal hypo or hyper T2 lesions with CE; seldom DWI hyper Lymphocytic pleocytosis; flow cytometry for lymphoma cells High LDH, ESR; biopsy Specific lymphoma treatment
Gliomatosis cerebri S Older adults AMS, dementia, seizures, headache, focal deficits T2/FLAIR hyper in 2+ lobes; +/- mass effect; +/- CE - Brain biopsy Radiation +/- chemotherapy

RPDs: Iatrogenic/Inborn Errors

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Medications A/S Older adults Attention to temporal relationship between initiating drug use and cognitive symptoms Nondiagnostic Nondiagnostic Nondiagnostic Discontinuation

Although most of the common neurodegenerative disorders do not present as rapidly progressive, they can present with this phenotype in certain cases.

RPDs: Neurodegenerative

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Creutzfeldt-Jakob Disease (CJD) S Mostly 50–70 years; M = F Subacute cognitive decline with behavioral, pyramidal, extrapyramidal, cerebellar, myoclonus, or visual symptoms Cortical or subcortical hyper on DWI Increased Total-tau, increased 14- 3-3, and increased NSE EEG: slowing; PSWCs See main article
Alzheimer's Disease (AD) S 60 years Early short-term memory impairment Hippocampal atrophy, later spreading to temporal, parietal, and frontal regions Decreased Aβ42, increased phospho-tau, increased total tau PET with amyloid ligand See main article
Lewy Body Dementia (LBD) S >50 years Cognitive dysfunction, parkinsonism, visual hallucinations, behavioral changes, fluctuations Normal or non- specific atrophy Nondiagnostic FDG-PET: occipital hypo See main article
Frontotemporal Dementia (FTD) S 40–70 years Behavioral changes (apathy, disinhibition, loss of empathy/sympathy, repetitive behaviors), executive dysfunction Frontal or temporal atrophy Nondiagnostic FDG-PET: frontal/ temporal hypo See main article
Corticobasal Syndrome (CBS) S 50-70 years Cognitive dysfunction, asymmetric motor abnormalities, or aphasia Asymmetric atrophy, parietal or frontal In AD etiology, decreased Aβ42, increased phospho-tau, increased total tau - See main article

RPDs: Systemic/Seizures

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Hypertensive encephalopathy A Uncontrolled hypertension, eclampsia, chemotherapy Headaches, confusion, visual changes, seizures, coma FLAIR hyper in occipitoparietal WM Nondiagnostic - Treatment of hypertension
Seizures A Older adults Cognitive dysfunction, fluctuations in alertness DWI hyper in cortical or subcortical GM Might have mild pleocytosis EEG AEDs
  • Bloodwork
    • CBC
    • Electrolytes, extended electrolytes
    • Liver function tests (including ammonia)
    • Renal function
    • Thyroid function
    • Anti-Tg (anti-thyroglobulin) and Anti-TPO (anti-thyroperoxidase) antibodies
    • Vitamin B12, MMA, homocysteine
    • Rheumatology screen (ESR, CRP, ANA (antinuclear antibody), RF (rheumatoid factor), C-ANCA (anti-neutrophil cytoplasmic antibody), P-ANCA, SSA, SSB)
    • Rapid plasma reagin (RPR)
    • HIV serology
    • Paraneoplastic/autoimmune antibodies
  • CSF
    • Cell count and differential
    • Protein
    • Glucose
    • IgG index
    • Oligoclonal bands
    • VDRL
    • 14-3-3/NSE (neuron-specific enolase)/total tau
  • Neuroimaging
    • Brain MRI (FLAIR, DWI, ADC sequences) +/- contrast
    • SPECT (to examine areas of hypoperfusion)
  • Other
    • Urinalysis
    • EEG

In Select Cases...

  • Other Bloodwork Considerations
    • Lyme disease (in endemic regions)
    • Cancer screening
    • Blood smear
    • Coagulation profile
    • Hypercoagulability testing
    • Copper, ceruloplasmin
    • Heavy metals screening (arsenic, lead, mercury, copper, aluminum and bismuth), in those with a history of exposure, or in those using herbal supplements.[18]
    • Additional rheumatological screen (complement, dsDNA, anti-Sm, anti-RNP, anticardiolipin, anti-SCL 70, anti-Jo, anti-centromere antibodies)
  • CSF
    • Bacterial, fungal, acid-fast bacilli stains and cultures
    • Cytology
    • Flow cytometry
    • Whipple PCR
    • Cryptococcal antigen
    • Viral PCRs and cultures
  • Imaging
    • Cancer screen (CT chest abdo pelvis +/- contrast)
    • MRI angiography or brain angiogram
    • MR spectroscopy
    • Carotid ultrasound
    • Echocardiogram
  • Urine
    • Heavy metal screen
    • Copper (24 hour urine)
    • Porphobilinogen (PGB)/delta-aminolevulinic acid (ALA)
    • EMG/nerve conduction study
    • Brain biopsy