Dementia: Pathology review

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Dementia: Pathology review



Dementia: Pathology review

USMLE® Step 1 questions

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USMLE® Step 1 style questions USMLE

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A 71-year-old woman is brought to the clinic by her partner due to worsening insomnia and cognitive impairment for the past 3 months. According to the husband, the patient had previously been able to drive to the grocery store and play racquetball. However, she is no longer able to complete these activities on her own. The patient has no history of psychiatric conditions, but her mother died from Alzheimer disease in her 80s. In the office, the patient’s temperature is 37.0°C (98.6°F), pulse is 88/min, respirations are 13/min, and blood pressure is 122/84 mmHg. Physical exam reveals ataxic gait and an inability to follow multi-step instructions.  When a nearby door is shut loudly, the patient is startled, causing her arms to clench involuntarily. Further evaluation of this patient is most likely to reveal which of the following findings?


At the neurology department, a 60 year old male, named Oliver, is brought in by his son because lately Oliver has become more aggressive, impolite and he seems to have lost his interest in his family. Recently, he has also started repeating conversations. Next, there’s a 72 year old female, named Iris, who is also brought by her son. Iris is always staying at home because she is embarrassed that she’s unable to hold her urine. She also has a hard time finding her things at home because she forgets where she has placed them. Her son has noticed that she is walking strangely, as if her feet stick to the ground. Finally, there’s a 35-year old male, named Alasdair, who is brought by his partner because in the past few weeks he has started repeating conversations and misplacing their belongings. Alasdair also has episodes of jerking movements of his left arm and he has fallen twice in the last few days. His medical history reveals corneal transplantation 6 months ago.

Okay, so all of these people have dementia. Dementia occurs when there’s a decline in at least one cognitive function and it impairs daily functioning. Remember that they need to have intact consciousness. Dementia can result from reversible and irreversible causes. Reversible causes include alcohol dependence, hypothyroidism, vitamin B12 deficiency, neurosyphilis, normal pressure hydrocephalus, or NPH, and depression. Irreversible causes include Alzheimer disease, which is by far the most common cause of dementia, vascular dementia, which is the second most common cause, frontotemporal dementia, Lewy body dementia, Parkinson disease, Huntington disease, and Creutzfeldt-Jakob disease, or CJD.

Okay, so let’s take a closer look at the irreversible causes of dementia, starting with Alzheimer disease, which is a very high yield topic for the exams! In the cell membrane of a neuron, there’s a molecule called amyloid precursor protein, or APP. Normally, old APP gets chopped up by two enzymes called alpha secretase and gamma secretase to a soluble peptide. But if another enzyme, called beta secretase, teams up with gamma secretase instead, then the chopped up fragment isn’t soluble, and creates a monomer called amyloid beta. For the test remember that these amyloid beta monomers bond together outside the neurons, and form beta-amyloid plaques. These plaques get between the neurons and impair brain function. Also, it’s important to know that amyloid plaque can deposit around blood vessels in the brain, causing amyloid angiopathy, which weakens the walls of the vessels and increases the risk of hemorrhage. Alright, now neurons are held together by their cytoskeleton, which is partly made up of microtubules, which also form tracks along the cell to ship nutrients and molecules. A protein called tau makes sure that these tracks don’t break apart. It’s thought that the beta amyloid plaques outside the neuron, initiate pathways inside the neuron that lead to activation of kinase, an enzyme that transfers phosphate groups to the tau protein. The tau protein stops supporting the microtubules, gets tangled with other tau proteins, forming neurofibrillary tangles inside the neuron. This makes Alzheimer disease a tauopathy. Okay, so remember, the tangles are found inside the cell, as opposed to the beta-amyloid plaques that are found outside the cells. Neurons with tangles and non-functioning microtubules can’t function, and end up undergoing apoptosis. The number of neurofibrillary tangles increases as the disease progresses. In addition, low acetylcholine levels in the nucleus basalis and the hippocampus also contribute to the cognitive symptoms seen in Alzheimer disease. This is due to impaired activity of an enzyme responsible for acetylcholine synthesis, called choline acetyltransferase in these areas of the brain.


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  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Adams and Victor's Principles of Neurology, Ninth Edition" McGraw Hill Professional (2009)
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  5. "Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment" Neurology (2007)
  6. "Genetics of dementia" The Lancet (2014)
  7. "Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy" Neurosurgical Focus (2015)
  8. "Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review" Brain Sciences (2017)
  9. "Current concepts and controversies in the pathogenesis of Parkinson’s disease dementia and Dementia with Lewy Bodies" F1000Research (2017)

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