Neurodegenerative diseases

Alzheimer's Disease: The Memory Thief

Alzheimer's disease results from the degeneration of a specific brain region called the nucleus basalis of Meynert. This area is located in the substantia innominata, just in front of the anterior commissure, and is particularly rich in acetylcholine - a crucial neurotransmitter for memory and learning. When this region deteriorates, the resulting loss of acetylcholine has been directly linked to the development of dementia.

The disease is characterized by two key protein abnormalities: abnormal amyloid precursor protein (APP), which leads to the formation of β-amyloid plaques, and hyperphosphorylation of the tau protein, which causes neurofibrillary tangles. These protein changes create the characteristic plaques and tangles that interfere with normal brain function, leading to the progressive memory loss and cognitive decline we associate with Alzheimer's.

Treatment involves Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) for mild to moderate cases. For moderate to severe cases, add Memantine (NMDA receptor antagonist).

• Grandma Doesn't Remember Me
  • Galantamine
• Donepezil
• Rivastigmine
• Memantine

Antidepressants can be used for depression (e.g. SSRIs). Avoid antipsychotics unless severe agitation (↑ mortality risk).

Huntington's Disease: A Family's Burden

Huntington's disease stems from the loss of GABA signaling due to atrophy of the caudate nucleus in the basal ganglia (leads to ventricular megaly). This devastating condition typically emerges between ages 30 and 60, beginning insidiously with psychiatric and cognitive symptoms. Interestingly, motor symptoms usually appear later in the disease progression.

One of the most recognizable features of Huntington's disease is chorea - a condition where patients experience restlessness and involuntary movements. Remarkably, many patients attempt to conceal these movements by transitioning them into purposeful actions. For example, if their hand moves involuntarily, they might smoothly convert that motion into brushing their hair back.

Huntington's disease also presents a unique phenomenon called anticipation. This means that future generations may develop the disease at a younger age or experience more severe symptoms than the previous generation. This occurs due to the expansion of CAG trinucleotide repeat sequences in the genetic code.

Treatment involves symptomatic management:

• Chorea:
  • Tetrabenazine (VMAT2 inhibitor)
• Deutetrabenazine (less sedating)
• Psychiatric symptoms:
  • SSRIs (e.g. sertraline)
• Antipsychotics if needed (e.g. risperidone)
• Genetic counseling

Creutzfeldt-Jakob Disease (CJD): The Rapid Destroyer

Creutzfeldt-Jakob disease is a rare but devastating human condition caused by the development of prions in the brain. Prions are misfolded proteins that, when they encounter other normal proteins, cause them to misfold as well - creating a cascading effect of protein damage.

This disease causes rapidly progressive dementia and ataxia (loss of coordination). The progression is alarmingly fast, typically leading to death within a year of onset. One specific and telling sign of CJD is spontaneous myoclonus - the development of shock-like jerks or twitching in muscles that occur without warning.

Medical testing reveals characteristic findings: EEG shows periodic epileptiform discharges, while brain tissue examination shows spongiform degeneration of the cortex. This creates holes in the brain tissue, giving it a distinctive sponge-like appearance.

Treatment is supportive with referral to palliative care if necessary.

Lewy Body Dementia: The Fluctuating Challenge

Lewy body dementia is often described as having Parkinson's-like symptoms, but with some key differences. Patients experience fluctuating cognition, where their mental clarity can vary significantly from day to day or even hour to hour. Unlike other forms of dementia, motor symptoms in Lewy body dementia typically present before or at the same time as cognitive symptoms. It is caused by the accumulation of alpha-synuclein protein in the brain, leading to the development of Lewy bodies.

Two distinctive features help identify this condition: dream enactment behavior (rapid eye movement sleep behavior disorder), where patients physically act out their dreams, and the presence of alpha-synuclein protein deposits in the brain.

Treatment of the symptoms involves:

• Cognitive:
  • Rivastigmine (cholinesterase inhibitor)
• Parkinsonism:
  • Levodopa (use cautiously, worsen psychosis)
• Hallucinations:
  • Quetiapine or clozapine (Atypical antipsychotics - least extrapyramidal side effects)
• Avoid typical antipsychotics → severe sensitivity (neuroleptic malignant-like reactions)

Frontotemporal Dementia: Personality Unraveled

Frontotemporal dementia (FTD) often starts with profound changes in personality, behavior, or language. It's a devastating condition that affects the frontal and/or temporal lobes of the brain - regions responsible for decision-making, social behavior, emotional regulation, and language.

In FTD, progressive degeneration of the frontal and temporal lobes leads to atrophy in these critical brain regions. The type of symptoms a person experiences depends on the specific area affected:

• Frontal lobe atrophy leads to changes in personality, impulsivity, and social disinhibition.
• Temporal lobe atrophy often presents with language deficits, such as difficulty speaking, understanding words, or naming objects.

Unlike Alzheimer’s, short-term memory is often preserved early on in FTD. Instead, caregivers might first notice that their loved one is behaving inappropriately, showing a lack of empathy, or compulsively repeating actions.

Like other neurodegenerative diseases, FTD is tied to abnormal protein accumulation. Three major culprits are: Tau protein (also seen in Alzheimer's and CTE), TDP-43 (also involved in ALS) and FUS protein. These misfolded proteins build up in neurons, disrupt function, and lead to cell death.

Unfortunately, there is no cure for FTD. Unlike Alzheimer’s, where cholinesterase inhibitors might help, these drugs are generally ineffective and can worsen behavioral symptoms in FTD.

Treatment focuses on symptom management:

• Behavioral changes:
  • SSRIs (e.g. sertraline, trazodone) may reduce disinhibition or compulsive behaviors.
• Agitation or psychosis:
  • Atypical antipsychotics very cautiously, due to risk of side effects.
• Supportive care:
  • Family education, caregiver support, and sometimes legal planning due to early onset.

FTD often strikes younger than other neurodegenerative diseases - commonly between ages 45 and 65