Prions: Could these zombie-like proteins be responsible for causing the most common form of Dementia?

Post courtesy of Dr Michael Chan, PGY2 Medicine Resident, Monmouth Medical Center.

ImageAs far as infectious diseases go, prions are a relatively new discovery. While humanity has known about parasites since ancient times, bacteria since the 1660s, and viruses since 1898, the first prion protein was only isolated in 1984. Since then, we’ve gotten to know a little more about these proteins, and we’ve found that its novelty is by no means the most interesting thing about it.
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So what are prions?

Prions are basically the misfolded version of a normal protein, PRP or Protease resistant protein. In the vast majority of instances, the body has mechanisms that adequately deal with misshapen proteins. These get tagged for destruction by antibodies or intracellularly by specific molecular signals and lysosomes. However, prions are not your run of the mill abnormal protein. They are resistant to degradation and exhibit the unique characteristic of causing other normal PRP proteins to misfold, which in turn causes even more misfolding. In this sense, prions behave like protein zombies.

And like zombies, they don’t begin their existence as malevolent molecules either. Indeed this is one of the characteristics which differentiate prions from most other infectious agents such as bacteria or viruses, majority of which are inherently disease causing. Studies have shown that normal PRP has functions in sleep, memory, neural development, and possibly the maintenance of the myelin sheath that surrounds neurons. Indeed, a mutation of PRP causes a very rare disease (only 8 cases have been diagnosed as of 2005) called Familial Fatal Insomnia which leads to progressively worse insomnia leading to dementia, hallucinations, and eventually death.

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Yes, complete inability to sleep kills.


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The connection to Alzheimer’s

Until recently, the most notable examples of prion diseases in humans are Creutzfeldt-Jakob disease and Kuru. Although spontaneous CJD does rarely occur, both these diseases are usually caused by ingestion of infected material, ie, eating infected meat (beef) for CJD and cannibalism for Kuru. Both exhibit progressive dementia, memory problems, gait and movement disturbances, and other unusual symptoms like uncontrolled laughter, hallucinations, and personality changes. Pathologically, the disease causes patients’ brains to develop tiny holes, much like a sponge. Thus the name for the disease in cows, Bovine Spongiform Encephalopathy, literally translates “cow spongy brain disease”.

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Brain of a CJD patient with multiple “holes”

However, over the past 5 years, research has shown that at least one major protein known to accumulate in Alzheimers disease, amyloid beta, behaves much like prions. Research conducted at UCSF showed that when mice brains are seeded with amyloid beta, after 300 days, the amyloid plaque is found all over the brain, not just the area seeded. A Yale university study in 2009 also showed that prion proteins of CJD interact with amyloid beta in some way to cause the dysfunction in neurons which lead to Alzheimer’s. Although there is no evidence that AD is contagious, it may open up new therapeutic avenues to think of its pathology as like that of prion diseases.

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Amyloid plaques and Neurofibrillary tangles in Alzheimer’s disease

How Alzheimer’s spreads in the brain.

Indeed, last year, a British team accidentally stumbled on a discovery that antibodies designed to treat CJD were found to block Alzheimer’s disease. These antibodies, ICSM-35 and ICSM-18, blocked the interaction between the PRP prion and amyloid beta in mice brains, resulting in decreased hippocampal nerve cell disruption. ICSM-18 and ICSM-35 are presently undergoing human trials for the treatment of CJD. With this finding, it’s likely they will be tested for Alzheimer’s as well, and we, for the first time, might have an effective and specific treatment for this disease which affects roughly 20 million people worldwide.

To see just how significant any form of treatment might be, check out the facts and figures provided by http://www.alz.org below:

References:

Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. 2011:70, 532–540.

Prusiner SB: A unifying role for prions in neurodegenerative diseases. 2012:336, 1511–1513.

Freir DB, Nicoll AJ, Klyubin I et alInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sitesNature Communications, June 7 2011

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Amnesia, it’s not just for soap operas

When people of think of amnesia, they usually first think of the mysterious stranger in a soap opera, who shows up in town after an accident or traumatic experience, having forgotten their own identity, and the efforts that ensue to uncover the missing information.

Actually, in medical practice this type of “soap opera” amnesia is psychogenic, a so-called psychogenic fugue state, very different from the amnesia seen with organic neurologic disorders like head trauma or stroke.

The character Dory in the 2003 Pixar Movie Finding Nemo is a better representation of organic neurologic amnesia – she has anteriorgrade amnesia and cannot retain new information, but remembers her name and other details of her own identity.

Another good example of organic anteriograde amnesia is the media is Leonard in the 2000 movie Memento,

It is thought that new memories are formed by a structure of the brain known as the Papez ciruit or limbic system, which includes the hippocampus, (subiculum), fornix, mammillary bodies, anterior thalamic nucleus, cingulum, and entorhinal cortex.

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Any lesion or process which interrupts this circuit will prevent the formation of new memories, leading to anteriograde amnesia.

Temporary Anteriograde amnesia can be caused by:

zzzzmedications, benzodiazepine anesthesia or “conscious sedation“,

zzzzhead trauma – post-traumatic amnesia or PTA,

zzzzand from Transient Global Amnesia (TGA).

TGA is a sudden onset of temporary anteriograde amnesia usually lasting lasting 4-12 hours.  It is often triggered by an emotional event or sexual intercourse.   During the episode, the affected patient is alert and lucid, cognizant of their own identity, but appears perplexed and may ask the same questions repeatedly.  The exact cause is unknown.  The recurrence rate is low.

More permanent anteriograde amnesia can be caused by:

zzzzinfarction of the hippocampi, as can be seen in the cardioembolic stroke syndrome “top of the basilar syndrome”,

zzzzbrain damage resulting from herpes encephalitis,

zzzzor from hemorrhage into the mamillary bodies – “Korsakoff’s psychosis”.

Korsakoff

Korsakoff’s psychosis is caused by thiamine deficiency, usually related to chronic alcoholism.  Affected patients have permanent anteriograde amnesia, and so they live in the past, and confabulate (make up details) to fill in the gaps in their memory.

Cortical Basal Ganglionic Degeneration

This post is provided courtesy of K. T. Weber, Drexel University College of Medicine Class of 2013:

Cortical Basal Ganglionic Degeneration (CBGD) is a rare neurodegenerative disorder that affects both the cerebral cortex and basal ganglia, resulting in a rapidly progressive and devastating combination of movement disorder and dementia.

CBGD shares features with other, more common, neurologic illnesses: Like Parkinson’s disease, it often presents asymmetrically, with a tremor, rigidity or dystonia. Like Alzheimer’s disease, there are subtle early cognitive and behavioral changes. However, CBGD progresses more rapidly than these other conditions, ultimately involving the other limbs and causing more cognitive dysfunction. Furthermore the Parkinsonian features of CBGD tend not to respond to dopaminergic medications.

Patient with CBGD, showing rigidity, paucity of movement, and myoclonic jerks in the left arm

One of the distinctive features of CBGD is alien limb phenomenon. Alien limb is characterized by a “loss of agency” in the affected limb. The patient is able to feel sensation in the limb, and movement is preserved, but the patient no longer recognizes the limb as his or her own. This same aLien limb or (more commonly an alien hand) syndrome can also result from separation or dysregulation between the brain’s hemispheres, for example after surgical division of the corpus callosum for severe epilepsy.

Patient with CBGD, showing rigidity, dystonic posturing and Alien limb phenomenon (the patient said the left arm was “moving on it’s own”)

In popular media, Dr. Strangelove struggled with an alien limb that was no longer under his control.

However, the movement disorder is only half the story, and symptoms also include behavioral changes, cognitive decline, and abnormal speech. Behavioral changes may involve personality changes, mood problems, like depression and agitation, or the development of new compulsive behaviors. Language problems often begin with difficulty finding words (“anomia“) and may progress to an inability to speak.

The disorder is currently classified as a “tauopathy” in the same family of diseases as Pick’s disease, progressive supranuclear palsy (PSP), and even Alzheimer’s disease.

Although the diagnosis of CBGD is mostly clinical, there are some diagnostic tests that may helpful, such as asymmetric cortical atrophy on brain imaging or asymmetric slowing on EEG.

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MRI showing right hemispheric atrophy

EEG showing L hemispheric slowing

EEG showing R hemispheric slowing

However, a definitive diagnosis can only be made by examining brain tissue at autopsy.

Pathology of CBGD (A) In the neocortex, ballooned neurons with displaced nuclei and pale cytoplasm (arrow) are common. (B) Immunostaining detects diffuse accumulations of tau protein in a peripheral distribution in a ballooned neuron. (C) Neuron loss and gliosis are often severe in deep nuclei, including the substantia nigra. (D) Diffuse cytoplasmic accumulation of tau protein is seen in neurons of various sizes in the neocortex (arrow, panel D), nucleus basalis (E) and striatum (F), as well as other locations. (Panels A,C from sections stained with H and E, remaining panels from sections immunostained with primary antibodies to tau).

Pathology of CBGD (A) In the neocortex, ballooned neurons with displaced nuclei and pale cytoplasm (arrow) are common. (B) Immunostaining detects diffuse accumulations of tau protein in a peripheral distribution in a ballooned neuron. (C) Neuron loss and gliosis are often severe in deep nuclei, including the substantia nigra. (D) Diffuse cytoplasmic accumulation of tau protein is seen in neurons of various sizes in the neocortex (arrow, panel D), nucleus basalis (E) and striatum (F), as well as other locations. (Panels A,C from sections stained with H and E, remaining panels from sections immunostained with primary antibodies to tau).

There are no effective treatments for CBGD, and therapy is aimed at symptomatic relief. The movement disorder, unlike Parkinson’s disease, does NOT respond well to levadopa, so other medications are used to help control the tremors and stiffness in the limbs. Beta blockers (propanolol), benzodiazepines (clonazepam), and gabapentin may have some efficacy in controlling tremor. Baclofen (a GABA agonist) is used to treat spasticity of many different causes and may provide some relief to patients with CBGD. Additionally, the depression, anxiety and agitation due to degeneration the cortical areas of the brain are critical therapeutic targets, and often respond to the first line therapies, including SSRIs and other antidepressants.

In summary, CBGD is a rare, progressive neurodegenerative disease. Recognizing the constellation of symptoms of CBGD from its more common cousins helps patients by identifying all elements of the disease progression, and can improve quality of life by addressing each of the related symptoms.

Diagnostic testing for Alzheimer’s?

The only definitive test for Alzheimer’s disease is examination of brain tissue (usually obtained at autopsy) for identification of the characteristic pathologic changes of Amyloid paque and Neurofibrillary tangles:
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Alzheimer’s disease is usually diagnosed based on  clinical criteria, but many patients diagnosed this way are later found to have other causes of dementia when their brains are examined at autopsy, in other words they were misdiagnosed as Alzheimer’s.

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With more effective new therapies on the horizon, it is going to become more important to establish a diagnosis of Alzheimer’s more accurately and earlier, perhaps even pre-symptomatically (i.e. mild cognitive impairment or MCI), so that treatment to reverse the build up of plaque and tangles is more likely to be effective.

There has been interest in Apoprotein E (APOE) genotype and Alzheimer’s risk. APOE genes come in 3 types (2-4).  If you have 2 copies of  APOE4 (1-2% of the population)  you are 15 times more likely to develop Alzheimer’s than averages, and if you have one copy of APOE4 you have are 3 times more likely to develop Alzheimer’s than average.   Clearly, there is an association between APOE4 genoytpe and Alzheimer’s.  However, not every patient with APOE4 develops Alzheimer’s, and you can develop Alzheimer’s without APOE4, so APOE genotyping is not recommended as a diagnostic test.

The ratio of cerebrospinal fluid levels of beta-amyloid and tau proteins can be predictive for Alzheimer’s, but this test requires a lumbar puncture, and is inconclusive in many cases.

Magnetic resonance imaging (MRI) of the brain has shown selective atrophy of the hippocampus in patients with early Alzheimer’s (a) vs. normal elderly controls (b), and this technique has been proposed as a diagnostic test for Alzheimer’s, but requires special computerized imaging processing not available at most imaging centers.
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Fluorodeoxyglucose posititon emission tomogrpahy (FDG-PET) shows reduced metabolic activity (uptake of sugar) in the temporal and parietal lobes of patients with early Alzheimer’s (these regions are darker) vs. normal elderly controls (these regions are brighter), and this test is FDA approved, covered by Medicare, and widely available at imaging centers around the counrty:
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A recent study compared the results of MRI, FDG-PET and analysis of CSF biomarkers  in 97 MCI patients, to see which was best for predicting who would convert to Alzheimer’s first. During a mean follow-up of almost 3-years, 43 patients progressed to AD and 54 did not. Of the 3 tests, an abnormal FDG-PET was most predictive.

Before you all rush out and get your FDG-PET to see if you are high risk for Alzheimer’s, be warned that results may be unreliable when the test is performed at an inexperienced center. Data presented at this year’s American Academy of Neurology meeting showed that up to 2/3 of patients referred to a University dementia program had been misdiagnosed with Alzheimer’s dementia based on misread FDG-PET scans performed at community imaging centers.

The Amyvid™ (Florbetapir F 18) PET scan, which was FDA approved this year, actually quantifies the amount of amyloid plaque in affected patients’ brains (bright), and is probably a more promising new PET technique for predicting Alzheimer’s disease. However, this test is not yet covered by Medicare or other insurance covering, and costs between $1500 and $3000:

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In sum, the hope for the future is that with earlier and more accurate diagnosis, future treatments could target Alzheimer’s in its earliest stages, before irreversible brain damage or mental decline has occurred.  However, it is clear that none of the available diagnostic tests are perfect, and although promising, amyloid plaque PET scans are not yet covered by Medicare, so for now we mostly continue to make do with clinical diagnostic criteria.

Normal Pressure Hydrocephalus

Normal pressure hydrocephalus (NPH) is caused by excessive accumulation of cerebrospinal fluid (CSF) and enlargement of the brain’s ventricular system, putting increased pressure on the surrounding brain tissue, and leading to a distinctive gait disturbance, urinary incontinence and mental decline.
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NPH can be effectively treated by a surgical procedure to divert the CSF from the ventricles into the peritoneal cavity via a ventriculoperitoneal shunt. Early diagnosis and treatment are important for this surgical treatment to be effective.

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However, many patients with dementia or gait problems and large ventricles on a brain imaging study will not improve after shunting.  Performing surgery on all such patients, without further selection, can result in ineffective surgery, and more importantly other potential complications like bleeding around the brain (a subdural hematoma).

Therefore selecting the patients with suspected NPH who are most likely to benefit from surgery is of the utmost importance.  Most patients with suspected NPH will first undergo a lumbar puncture to measure the CSF pressure, and then drain off excess fluid, temporarily lowering the pressure.  If they improve after this procedure they will usually be referred for placement of a permanent ventriculoperitoneal shunt.

However, “improvement” after lumbar puncture is generally assessed subjectively, and can be very transient.  Some NPH patients who do not improve after lumbar puncture do still benefit from a shunting procedure.  Studies have shown that careful evaluation of patients using objective measures during prolonged CSF drainage via a lumbar drain is the most sensitive and specific way to predict which patients will improve with surgery.

The Monmouth Neuroscience Center  has developed a multidisciplinary hydrocephalus assessment program to evaluate patients with suspected NPH and determine who is most likely to benefit from a shunting procedure.  Patients are admitted to the intensive care unit, where a sterile lumbar drain can be placed to continuously drain CSF over 1-3 days, while they are carefully evaluated by our multidisciplinary team of neurologists, neurosurgeons and physical therapists for improvement in memory and gait using objective measures including videotaped gait analysis.

At the conclusion of the procedure, the drain is removed, and patients can review this data with their doctors to decide whether they might benefit from elective re-admission for placement of a permanent ventriculoperitoneal shunt.  Our surgeons implant  shunts with magnetically programmable valves allowing easy access to fine tune shunt function over time.  Patients are regularly followed by our team of neurologists and neurosurgeons, with ongoing adjustment of the valve in the shunt using an external programming device to ensure the correct rate of CSF drainage, to maximize neurologic improvement and minimize complications.

Click here for more examples of neurogenic gait disorders. For more information about the NPH program at Monmouth Neuroscience Institute, please visit our website, or call us at (732) 923-5576