AssessmentsDementia: Pathology review
USMLE® Step 1 style questions USMLE
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?
Content Reviewers:Yifan Xiao, MD
Contributors:Elizabeth Nixon-Shapiro, MSMI, CMI, Sam Gillespie, BSc, Maria Emfietzoglou, MD, Jung Hee Lee, MScBMC
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.
Okay, now Alzheimer disease can be either sporadic or familial. Sporadic is used to describe the late-onset type which is probably a combination of genetic and environmental risk factors, and accounts for the majority of cases. A gene that’s been identified as possibly contributing is the e4 allele of apolipoprotein E gene, or APOE-e4. Apolipoprotein E helps break down beta-amyloid, but the e4 allele seems to be less effective than the other alleles, meaning patients are more likely to develop beta-amyloid plaques. Okay, now familial Alzheimer disease is used to describe cases with early onset Alzheimer. This can be caused by several gene mutations, and accounts for about 5 to 10% of cases. For example, mutations in the PSEN-1 or PSEN-2 genes on chromosome 14 or chromosome 1, respectively, have been linked to early-onset Alzheimer’s. These genes encode for presenilin-1 and presenilin-2, both protein subunits of gamma-secretase. Mutations in these genes change the location where gamma secretase chops APP, producing different length beta amyloid molecules, which seem to be better at clumping up and forming plaques. Another known genetic cause of Alzheimer is trisomy 21, or Down syndrome. The gene responsible for producing APP is located on chromosome 21, which means that individuals with Down syndrome have an extra APP gene potentially increasing the amount of amyloid plaque buildup.
Next up is vascular dementia, where there’s a progressive loss of brain function caused by long term poor blood flow to the brain. Vascular dementia develops when atherosclerosis starts to form in the arteries supplying the brain, like the internal carotid arteries. This leads to a gradual decrease in blood flow to the brain, which is called chronic ischemia. Sometimes, small parts of the plaques can break away, and can then eventually block a smaller artery, completely stopping the blood supply to the parts of the brain. Other times, the tiny perforating arteries are affected by atherosclerosis and can get completely blocked off by plaque growing within them. Regardless of the cause, once blood supply to the brain falls below the demands of the tissue, it’s considered an ischemic stroke. The tissue damage from an ischemic stroke is usually permanent, and the dead tissue liquefies in a process called liquefactive necrosis. Brain tissue necrosis leads to a loss of mental functions governed by that area. Now, if another stroke happens later on, more brain tissue might die off, over time this damage gets worse and worse, and the final result is dementia. This is referred to as multi-infarct dementia and it’s a subtype of vascular dementia that you have to remember for the exams!
Next is frontotemporal dementia. For the test, remember that frontotemporal dementia refers to atrophy of the frontal lobes that eventually progresses to the temporal lobes, with relative sparing of the parietal and occipital lobes. A high-yield subtype of frontotemporal dementia is Pick disease, which is characterized by the presence of Pick bodies, which are tangles of tau proteins. Tau comes in different isoforms, like the 3R and the 4R isoforms. In Pick disease, 3R isoforms get hyperphosphorylated, change shape and stop being able to tie together the microtubules in the neuron's cytoskeleton. They also start clumping together, forming tangles. So Pick disease is a tauopathy, like Alzheimer disease. A key difference is that the tangles in Pick disease, are called Pick bodies, and they’re only made up of the 3R isoforms, whereas the neurofibrillary tangles in Alzheimer disease are made up of both 3R and 4R tau isoforms. Now, neurons with loads of tangles and non-functioning microtubules don't function well, and the neurons undergo apoptosis.
Okay, now next is Lewy body dementia. The underlying cause of Lewy body dementia isn’t well understood. Normally, neurons contain a protein called alpha synuclein, and in Lewy body dementia, this protein get misfolded within the neurons. The misfolded alpha-synuclein aggregates to form Lewy bodies that deposit inside neurons, particularly in the cortex and the substantia nigra. Under a microscope, Lewy bodies look like dark, eosinophilic inclusions inside the affected neurons. As the disease progresses, more and more neurons accumulate Lewy bodies and die. The significance of Lewy bodies, however, is unknown, but remember that they’re also seen in other diseases like Parkinson disease.
Alright, now Parkinson disease can also cause dementia. This is a slowly progressive genetic disorder that primarily affects individuals over 50 years old. It’s characterized by the loss of dopamine-producing, or dopaminergic, neurons in the substantia nigra, which is a part of the basal ganglia. Normally, within the basal ganglia there’s a balance between dopamine, which promotes movement, and acetylcholine, which inhibits movement. In Parkinson disease, the loss of dopaminergic neurons, results in less movement, difficulties in speech and swallowing, as well as cognitive symptoms, like dementia in the later stages of the disease.
Next, there’s Huntington disease, which is very high yield! So, Huntington disease is an autosomal dominant neurodegenerative disorder that typically affects individuals around 40 years of age. It is caused by a mutation in the Huntington disease, or HD, gene on chromosome 4. This gene contains a CAG trinucleotide repeat, which encode for the amino acid glutamine, The gene encodes for a protein called huntingtin. The mutated protein aggregates within the neuronal cells of the caudate and putamen of the basal ganglia, causing neuronal cell death. So, the caudate and the putamen of the basal ganglia are the areas of the brain affected in Huntington disease. The brain regions affected by Huntington disease have decreased GABA and acetylcholine and increased dopamine levels. There’s also excessive activation of a subtype of glutamate receptors, called NMDA receptors, that leads to glutamate excitotoxicity, a process by which neurons are damaged. Over time, if enough neurons die in the caudate and putamen, which together form the dorsal striatum, this can cause actual loss of brain tissue volume in these areas, which can expand to the lateral ventricles. These areas of the brain play an important role in movement, particularly, inhibiting it, and that’s why Huntington disease causes movement problems like chorea and athetosis. But they also have cognitive symptoms, like dementia. Alright, now another high yield concept about Huntington disease is a phenomenon called anticipation, which is where there’s an increased number of trinucleotide repeats in subsequent generations. This leads to an earlier onset and more severe presentation of the disease. This process of adding more repeats is called repeat expansion. It happens way more in the production of sperm than eggs, and so anticipation generally occurs when the biological father is the affected parent.
Finally, a rare cause of dementia is Creutzfeldt-Jakob disease, or CJD. CJD is the most common cause of spongiform encephalopathy and it’s a high yield topic for the exams! Spongiform encephalopathy refers to a group of neurodegenerative diseases caused by the accumulation of infectious, misfolded prion proteins, called prions. Misfolded means that they change from having mostly α-helices to having a lot of ß pleated-sheets and so, they become resistant to being broken down by proteases. When a misfolded prion protein enters the neuron, it induces the misfolding of the normal prion proteins found inside the neuron. As a result, prions accumulate within the neuron and trigger apoptosis with the help of an intracellular 14-3-3 protein. When large numbers of neurons die, the brain gets replaced by cysts making it look like a sponge. That’s why these diseases are called spongiform encephalopathies.
Now, there are actually four types of CJD; familial or fCJD, variant or vCJD, iatrogenic or iCJD, and sporadic or sCJD. Familial Creutzfeldt-Jakob disease occurs when there’s a mutation in the PRNP gene which encodes for the prion protein. Variant Creutzfeldt-Jakob disease is caused by eating the meat of cows with prions in the muscle tissue. In cows, these prions cause bovine spongiform encephalopathy, which is more commonly called “Mad cow disease.” When sheep are fed cow meat, the prion causes the disease Scrapie. If a person eats the meat of affected cows or sheep, the prions get absorbed through the intestines into the bloodstream. The protein can somehow get through the blood brain barrier and then enters neurons by a process called adsorptive endocytosis. Adsorptive endocytosis is a process where the plasma membrane of nerve cells folds inwards to bring in substances that otherwise would not be able to cross the plasma membrane by themselves. Iatrogenic Creutzfeldt Jakob disease is caused by medical procedures, like a corneal transplant, where the transplanted organ or the instruments gets contaminated by prions. Finally, there’s sporadic Creutzfeldt-Jakob disease which pops up in populations randomly without a clear cause.
Now let’s quickly go over the reversible causes of dementia. Common ones include chronic alcohol use, hypothyroidism, vitamin B12 deficiency, or tertiary syphilis. Another important reversible cause is depression, and cognitive impairment due to depression is referred to as pseudodementia. A key finding in pseudodementia is that individuals are often anxious about their memory impairment as opposed to other causes of dementia, like Alzheimer disease. A very high yield reversible cause of dementia is normal pressure hydrocephalus, or NPH. NPH typically occurs in the elderly so it’s often misdiagnosed as Alzheimer disease. It’s caused by abnormal venous drainage of the cerebrospinal fluid, resulting in hydrocephalus. Since the frontal lobe is the most affected, Individuals with NPH usually present with urinary incontinence and gait disturbance at first, and then dementia.
Alright, now let’s switch gears and talk about clinical presentation. Although all these disorders can cause dementia, many of them also cause other symptoms that will be key clues for the correct diagnosis. But before that, let’s take a look at how dementia typically presents. Most of the time, a close family member or friend notices the individual’s change in cognition. This includes impaired memory, which leads to repeating conversations or misplacing belongings. Language impairment can make it hard to think of common words. Additionally, concentration and executive function are impaired, so individuals have a hard time with complex tasks, like managing their finances. Visuospatial impairment can prevent them from recognizing faces and navigating in familiar locations. Sometimes, family members also notice changes in the individual’s personality.
Okay, now there are specific symptoms that can help you identify the different causes of dementia. For the exams remember that Alzheimer disease has an insidious onset and gradual progression. Individuals usually go through 3 phases. First is the asymptomatic phase. Second is a predementia phase called mild cognitive impairment, during which there’s gradual onset of memory impairment without much impairment in other cognitive domains, and no impairment in daily functioning. This differs from normal aging, because the memory impairment is greater than expected for the individual’s age. The third phase is the dementia phase, and that’s where individuals develop more significant memory loss, followed by slow, gradual loss of the other cognitive functions, such as language, visuospatial, and executive functions. Now, there are two main types of memory: episodic memory, which is memory of events, and semantic memory, which memory of words and vocabulary. Early on, episodic memory is impaired and semantic memory remains intact. Later on, both episodic and semantic memory get impaired. Episodic memory can be subclassified into immediate, recent, or long term. Immediate memory is sometimes called procedural memory, and it’s the memory that you use to repeat back a phone number right away. Recent memory is the memory you use to remember a list of three words five minutes later, like those 3 words from earlier. This is the type of memory that’s impaired early on in Alzheimer disease because the disease affects the hippocampus first, which is responsible for recent memory. Long-term memory is the memory of events that have occured years ago, and these are not impaired until late in the course of this disease. For example, an individual with Alzheimer may remember the details of their wedding 50 years ago, but they won’t be able to remember where they were yesterday.
Okay, now symptoms of vascular dementia vary depending on which region of the brain is damaged. For example, if someone has strokes in the temporal lobe, it might be difficult for them to remember things or make new memories. Someone with a stroke in the left parietal lobe might lose the ability to speak, which is called an aphasia. But then if they get another stroke in the frontal lobe, their personality might begin to change. One thing that’s constant, is that the symptoms of dementia appear suddenly and brain function decreases with each stroke. Another characteristic finding in vascular dementia is that individuals have neurological deficits which correspond to the region of the brain that’s affected by the stroke. They can also have other manifestations of atherosclerosis, like coronary artery disease, and other comorbidities that increase the risk of stroke like hypertension and diabetes. Now, in multi-infarct dementia, there’s a characteristic stepwise decline in cognitive function. For example, the individual develops a stroke, and as a consequence demonstrates a sudden decline in their memory. Then, in between stroke events, there is no progression of their cognitive dysfunction, until another stroke occurs, and they suddenly lose another cognitive domain such as language, and so on. This pattern, alongside a temporal relation to the stroke, is what differentiates it from Alzheimer disease where the decline in cognitive function is steady and gradual. Also, unlike in Alzheimer disease where recent memory is usually lost first, the pattern of cognitive decline in vascular dementia varies depending on which area was infarcted.
Individuals with frontotemporal dementia usually present before the age of 65 and it is very important to remember for the test that early on they have behavioral symptoms, with relative sparing of memory defects. These symptoms include personality changes, impaired judgement, apathy and disinhibition. They also have perceptual-motor function loss, meaning individuals struggle with things like hand-eye coordination or body-eye coordination. There are two variants of frontotemporal dementia. In the behavioral variant, first there are three or more of the following five symptoms: disinhibition; apathy or inertia; loss of sympathy or empathy; stereotyped, compulsive or ritualistic behavior; hyperorality which when people put inappropriate objects in their mouth, and dietary changes. And second, there is a decline either in social cognition or in executive abilities which are a set of skills necessary to adapt to the environment and to achieve goals. The language variant is when there’s a prominent decline in language skills, or aphasia. Individuals have difficulty in speech production, word finding, object naming, grammar, or word comprehension.
Okay, now two very similar types of irreversible dementia syndromes are Lewy body dementia and Parkinson disease dementia. Both include dementia and “parkinsonism”, a term used to describe the movement disorder in both diseases. The symptoms of parkinsonism can be remembered with the mnemonic “TRAP”. “T” for tremor, “R” for rigidity, “A” for akinesia or bradykinesia, which is absence or slowness of movement, and “P” is for postural instability. Lewy body dementia is distinct from dementia secondary to Parkinson disease in that the onset of dementia occurs before the onset of motor symptoms, and this takes place less than one year apart. In Parkinson disease, motor symptoms develop first and it can take many years before the onset of dementia. Other features of Lewy body dementia include recurrent episodes of having vivid visual hallucinations, and fluctuating, episodic deficits in attention and alertness, which may be confused with delirium. In addition, individuals with Lewy body dementia can have sleep behavior disorder, where individuals move a lot while sleeping.
Okay, now, in contrast to parkinsonism, individuals with Huntington disease often have chorea, which are involuntary, random, rapid, dance-like movements, or athetosis, which are slower, writhing, “snake-like” movements that mainly affect the hands. They can also have psychiatric symptoms like depression, psychosis or aggressive behavior. Death usually occurs within 10–20 years of diagnosis, often by aspiration pneumonia, on account of discoordinated swallowing, or by suicide.
Now, for the test remember that individuals with CJD has a long incubation period but after the onset of symptoms individuals develop rapidly progressive dementia within weeks to months. It is also classically associated with ataxia, which is defined as lack of coordination of voluntary movements and myoclonus, a jerking movement of a muscle group. Hiccups are an example of myoclonus. In CJD, the myoclonus is usually generalized and can be triggered when the person is startled, and that’s why it’s referred to as “startle myoclonus”. CJD eventually leads to death since there’s currently no cure.
Finally, for NPH, remember that it affects the elderly and symptoms can appear over a month and presents with dementia, urinary incontinence and gait disturbance. Their gait is described as “magnetic”, because it seems like the person’s feet are glued to the ground.
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