36. Dementias and neurodegenerative disorders

Dementia

Dementia is a clinical condition where there is loss of higher cognitive functions like thinking, remembering and reasoning, to the extent that it interferes with a person’s daily life. It is most common in elderly and affects 10% of people above 65. It’s important to keep in mind that dementia is not a part of normal aging.

Commonly affected functions include:

• Orientation
• Problem solving
• Concentration
• Attention
• Personality
• Memory
• Language
• Reading/writing
• Emotions

Although dementia can affect a variety of different functions, the most characteristic symptom is probably forgetfulness.

Many conditions can cause dementia:

• Neurodegenerative diseases
  • Alzheimer disease
  • Frontotemporal lobar degeneration
  • Lewy body dementia
  • Parkinson disease
  • Huntington disease
• Infective disorders
  • Neurosyphilis
  • HIV dementia
  • Progressive multifocal leukoencephalopathy (PML)
• Prion diseases
  • Creutzfeldt-Jakob disease
  • Variant Creutzfeldt-Jakob disease
• Cerebrovascular diseases – vascular dementia
  • Multi-infract dementia
  • Hypertensive encephalopathy
  • Carotid sinus hypersensitivity
• Trauma
  • Chronic traumatic encephalopathy/dementia pugilistica
• Metabolic diseases
  • Thiamine deficiency (Wernicke-Korsakoff syndrome)
  • B12 deficiency
  • Niacin deficiency (pellagra)
  • Chronic alcoholism
  • Liver disease
  • Mercury/lead poisoning
• Other
  • Storage diseases
  • Porphyria

Vascular dementia

Vascular dementia refers to dementia that occurs due to cerebrovascular diseases. They involve intermittent or chronic ischaemia of the brain parenchyme.

The most important causes are:

• Multi-infarct dementia – recurrent cerebral infarcts
• Status lacunaris – multiple subcortical infarcts
• Binswanger disease – arteriosclerosis and thromboembolism of vessels that supply the white matter
• Cerebral amyloid angiopathy – due to Aβ amyloid deposition in blood vessel walls
• CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

Multi-infarct dementia is dementia that occurs in patients who experience multiple cerebral infarcts, often due to atherosclerosis of the carotids and/or embolization. Binswanger disease is similar but affects the vessels that supply the white matter and not the cortex.

CADASIL is the most common form of hereditary stroke disorder. It occurs due to progressive hypertrophy of the smooth muscles of the blood vessels, which increases the risk for developing transient ischaemic attacks and strokes.

Traumatic dementia

The most important form of traumatic dementia is chronic traumatic encephalopathy (CTE), which is nowadays considered to be the same as dementia pugilistica. Dementia occurs years after recurrent head traumas, often seen in people who do contact sports like boxing and American football.

The pathogenesis involves axonal injury, micro-haemorrhages and loss of local blood-brain barrier integrity. The histology of CTE is similar to that of Alzheimer disease, in that both involve deposition of tau protein, forming neurofibrillary tangles.

Metabolic dementia

The two most important forms of metabolic dementia are Wernicke-Korsakoff syndrome and hepatic encephalopathy.

Wernicke-Korsakoff syndrome is the presence of both Wernicke encephalopathy and Korsakoff syndrome in the same patient. Both are caused by thiamine deficiency and are frequently seen in chronic alcoholics. Wernicke encephalopathy involves psychosis and ophthalmoplaegia (weakness of extraocular muscles) while Korsakoff syndrome involves memory alterations and confabulation.

Hepatic encephalopathy occurs when there is liver failure. This will cause encephalopathy by many mechanisms, one of which involves hyperammonaemia. A special type of tremor called asterixis is common on these patients.

Neurodegenerative diseases

Neurodegenerative diseases are disorders where there is cellular degeneration of a specific subtype of neurons. Many of these disorders are associated with accumulation of abnormal proteins, which can be detected by histology. The cause of these disorders isn’t really known.

The most important ones are:

• Alzheimer disease
• Frontotemporal dementias
  • Pick disease
• Parkinson disease
• Huntington disease
• Amyotrophic lateral sclerosis (ALS)

Alzheimer disease

Alzheimer disease is the most frequent cause of dementia, especially in elderly. It occurs in 40% of people above 85 years old. The mean age is 80 years.

The majority of cases are sporadic, while around one quarter of cases are familial.

Certain risk factors are known:

• Gene mutations
  • In the APP gene
  • In the ApoE gene
• Old age
• Family history of dementia
• Down syndrome
• Lack of physical activity

The morphology of Alzheimer disease involves:

• Brain atrophy – especially of the temporal, frontal and parietal lobes
• Neurofibrillary tangles
• Senile/neuritic plaques
• Hirano bodies
• Granulovacuolar degeneration

The exact pathogenesis of Alzheimer disease isn’t known; however we do know how the beta amyloid plaques and neurofibrillary tangles develop. A transmembrane protein called amyloid precursor protein (APP) is cleaved into an Aβ monomer. These monomers aggregate and form amyloid senile plaques that deposit extracellularly. The formation of these fibrils causes a protein called tau to be hyperphosphorylated, which causes the protein to deposit and form intracellular neurofibrillary tangles.

The gene for APP lies on chromosome 21, which explains why people with Down syndrome (trisomy 21) have increased risk for developing Alzheimer.

The pathological changes are firstly seen in the hippocampus and parahippocampal cortex, but in the later stages they will be apparent in the whole cortex. Neurofibrillary tangles aren’t characteristic only for Alzheimer; conditions that involve abnormal hyperphosphorylation of tau are called “taupathies”. Senile plaques are characteristic for Alzheimer.

The most common earliest symptom of Alzheimer is short-term memory loss, however the disease progresses to affect more cognitive functions. The mean life expectancy is 7 years. The disease progresses faster in people who get the diagnosis at a younger age.

An overall reduction of cholinergic function occurs in Alzheimer disease and is believed to be a cause of dementia. Acetylcholinesterase inhibitors may be used to improve symptoms.

Frontotemporal dementias

The frontotemporal dementias are caused by the pathological changes called frontotemporal lobar degeneration. It is a heterogenous group of syndromes that involve degeneration of the frontal and/or temporal lobes, and manifest with several symptoms of dementia. It most frequently affects people between 40 and 60, and it’s the most frequent cause of dementia in this age group. Frontotemporal dementias are taupathies.

Pick disease is a subtype of frontotemporal dementias. The name of this subtype comes from the presence of smooth, round inclusion bodies called Pick bodies.

The symptoms depend on which lobes are affected most:

• Frontal lobe affected most
  • Personality changes
  • Behavioural changes
• Temporal lobe affected most
  • Aphasia

Intelligence and memory typically aren’t affected until the later stages.

Parkinson disease

Parkinsonism is a syndrome that involves bradykinesia (slow movements), tremors, rigidity and instability. It has many causes, of which Parkinson disease is the most common cause. The other causes include:

• Medication (drug-induced parkinsonism)
  • Antipsychotics (like haloperidol)
  • Antiemetics (like metoclopramide)
• Toxins
• Metabolic diseases
  • Wilson disease
• Cerebrovascular diseases
• CNS infections
• Other neurodegenerative disorders (Parkinson-plus syndromes)
  • Multiple system atrophy
  • Progressive supranuclear palsy
  • Corticobasal degeneration
  • Creutzfeldt-Jakob disease

Parkinson disease involves a progressive depletion of dopaminergic neurons in the basal ganglia, especially in the substantia nigra. It is a synucleinopathy, meaning that it involves deposition of a protein called α-synuclein. Familial cases of Parkinsons disease have been linked to mutations in genes of PARK7,PINK1, LRRK2 and PARKIN.

Depigmentation of the substantia nigra is characteristic. Histology shows Lewy bodies, which are intracytoplasmic eosinophilic inclusions.

Huntington disease

Huntington disease is characterized by involuntary and irregular movements of the limbs, neck, head and/or face. These movements are called choreas. It is autosomal dominantly inherited. Degeneration of the striatum (caudate nucleus and putamen) is characteristic.

The cause of Huntington disease is known. The gene for a protein called huntingtin is found on chromosome 4. This gene normally contains 6 – 35 copies of the trinucleotide CAG. When the gene contains around 40 or more CAG repeats development of Huntington is almost certain. The actual number of CAG repeats strongly correlates with how early the disease begins. The number of CAG repeats may reach many hundred. A malfunction of DNA polymerase is most likely the cause for this trinucleotide expansion.

The trinucleotide CAG corresponds with the amino acid glutamine, so the huntingtin protein in these cases will contain a tract consisting of glutamine. This mutant protein is subject to ubiquitination and proteolysis, yielding small fragments that aggregate and damage the neurons.

Symptoms of Huntington disease commonly begin in the 40s. In the early stages is chorea the most common symptom, while in the later stages hypokinesis, rigidity and dementia dominate.

The pathological changes are atrophy of the caudate nucleus and putamen. Immunohistology shows intranuclear inclusions containing ubiquitin.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the only neurodegenerative disease on this list that doesn’t just affect the brain. It was made famous by the ice bucket challenge phenomenon that was viral in 2014. It involves neurodegeneration of upper motor neurons (Betz pyramidal cells) in the motor cortex and of lower motor neurons in the anterior horn of the spinal cord and brain stem.

ALS is more common in men and occurs in the age of 50 – 60. Most cases are sporadic but 10% of cases are familial. The average life expectancy is just 3 – 5 years. The cause is unknown. Mutations in the gene for superoxide dismutase are found in a small number of affected people.

The loss of upper motor neurons causes paresis (weak movements), hyperreflexia,and babinski sign, while the loss of lower motor neurons causes denervation of the muscles with resulting weakness and eventually muscular atrophy (amyotrophy). The loss of upper motor neurons also causes degeneration of the corticospinal tracts in the lateral portion of the spinal cord, hence the “lateral sclerosis”.

Death occurs due to respiratory failure and dysphagia. Dementia is common in the later stages.

The pathological changes are atrophy of the ventral roots of the brain stem, loss of anterior horn neurons (lower motor neurons), and loss of neurons in the brainstem and motor cortex. Bunina bodies are found, which are eosinophilic inclusion bodies in lower motor neurons.