CJD – A downward spiral of depression into dementia and death

Post prepared by Dr Mariam Kemal, PGY-3 (Internal medicine), Monmouth Medical Center

Case History:

This 66 year old female had been living alone independently.  However, her neighbors became concerned when she had seemed more withdrawn than usual for about a month, and then stopped going out of the house and paying her utility bills.  Ultimately, one of them  noticed a dead cat in the house, and immediately called patient’s son who lived out-of- state, and he requested that she be admitted hospital.  At the time of her initial evaluation, she was depressed and had a urinary tract infection.  She was treated for the infection, and when she expressed suicidal ideation she was transferred to the psychiatric unit. While she was on the psychiatric unit she developed slurred speech, right arm clumsiness and and unsteady gait.   She was transferred back to the medical service and underwent a diagnostic evaluation.   Her brain MRI showed diffusion restriction in left putamen and caudate nucleus. Her EEG was also abnormal.  Her spinal fluid was ultimately positive for presence of Protein 14-3-3, indicating Creutzfeldt –Jacob disease.  She has progressed to a very debilitated state in just two week – Her speech was limited to a few intermittent slurred words, she was not able to walk and had diffuse myoclonic jerks. She was transferred to hospice.  Her brain was sent for autopsy to The National Prion Disease Pathology Surveillance Center which confirmed the presence of abnormal protease resistant prion protein (PrPSc), commonly identified as PrP 27-30, confirming the diagnosis of sporadic Creutzfeldt-Jacob disease.
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What is Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease (“CJD”) is a rare brain disorder that causes rapidly progressive dementia with muscle twitching, leading to death within several months.

CJD usually affects older adults.


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It is caused by abnormal proteins called “prions” that infect the brain.

“Classic” CJD has been transmitted by infected organs during transplant surgery.

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“Variant” CJD (“mad cow disease”) has been transmitted by infected beef.

In addition to dementia and myoclonus, many CJD patients also exhibit behavioral change (including depression), balance problems, and sleep disturbance.

It is the presence of these unusual clinical features, and the rapid rate of clinical deterioration, that distinguish CJD from other dementias like Alzheimer’s disease.

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How is Creutzfeldt-Jakob disease diagnosed?

MRI imaging of the brain can show characteristic findings:

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The electroencephalogram (EEG) can show periodic complexes:

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The spinal fluid can show the 14-3-3 protein.

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However, a brain biopsy demonstrating spongiform change is still necessary to confirm the diagnosis in many cases:

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How is Creutzfeldt-Jakob disease treated?

Sadly, there are no treatments that can stop or cure the disease, and all affected patients die within several months.

Playing video games improves aging brain function

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We know from previous blogs that there is an escalating incidence of dementia.

We know that the strongest risk factor for developing dementia is old age.

However, we also know that dementia is not an inevitable consequence of old age.

Why do some older adults get dementia and others don’t?

Instead of looking for dementia risk factors, some researchers have turned the tables on this question, and looking at things that might be protective, reduce the likelihood of age related dementia.

This could translate into activities or behaviors  anyone could use to lower their dementia risk.

For example, regular exercise and social stimulation have been shown to lower dementia risk.

New research published in Nature looks at the relationship between brain function and video games performance in aging adults.

The investigators designed a game called NeuroRacer in which the player drives a virtual car along a track and must respond to the appearance of specific road signs by pressing a button. The trick is that the player has to attend to one type of sign only, ignore the others, and continue “driving” all the while.  Then, as the participants learned the game and improved their scores, the game gets harder and harder.

neuroracer

The study had 46 participants, aged 60-85, engage in 12 hours of the training over the course of a month. During that time, they vastly improved their performance, and at the end of that study they played just as well as 20-year olds.  Furthermore, these gains in brain function persisted for more than 6-months, and more importantly weren’t limited to gaming – study participants also showed improved attention and working memory.

Click here to find out more.

New cure for dementia?

Probably not.

However, this study does demonstrate that older adults can still re-shape their brain connections, and also re-affirms that the old adage, if you don’t use it you lose it, also includes brain function!
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Maybe it’s time to start playing chess or BrainAge regularly?

Memory Loss? Better check that medication list!

Memory Loss

Alzheimer’s disease is the commonest cause of memory loss and dementia.   We do not yet fully understand what causes Alzheimer’s.  However, we do know that the neurotransmitter acetylcholine is important in brain processing and memory.  We also know that the acetylcholinesterase inhibitors (drugs like Aricept<donezepil> , Exelon <rivastigmine> and Razadyne <galantamine>), which inhibit the breakdown of acetylcholine, do provide a symptomatic improvement in affected patients.

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acetylcholine

 

It is also known that many drugs can cause and/or exacerbate memory loss in elderly patients:

Anticholinergics block the effects of acetylcholine, causing confusion. They also negate the beneficial effects of aceylcholinesterase inhibitors in Alzheimer’s patients.  These drugs are commonly prescribed for urinary frequency and urgency, and include Ditropan <oxybutynin> and Vesicare <solifenacin>.  The tricyclics, including Elavil <amitriptyline> and Pamelor <nortriptyline>, commonly prescribed for insomnia and headaches, also have anticholinergic properties.

Benzodiazepine drugs like Xanax <alprazolam> Restoril <temazepam> and Klonopin <clonazepam>, most commonly prescribed for anxiety and insomnia, can also cause and/or exacerbate memory loss because of drowsiness and inattention.

A recent study of Alzheimer’s patients living independently in the community showed that as many 17% were taking anticholinergic drug and almost 9% were taking benzodiazepines.

As if that wasn’t bad enough, 16% of patients were taking both an acetycholineresterase (cholinergic) and an anticholinergic drug at the same time!

The bottom line here is that you should always bring a complete and updated list of all your medications with you to doctors appointments!

med list

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Click here for a link to the full article.

New Brain Imaging for Alzheimer’s Disease

Amyloid proteins in normal brains (left) and abnormal ones (right) visualized with GE Healthcare’s PET tracer flutemetamol.

Alzheimer’s disease is the commonest cause of dementia, and as the population is aging, it’s prevalence is increasing.

Alzheimer’s disease presently affects 5 million Americans aged 65 or older.  Without a major medical breakthrough, by 2025 this number is expected to have risen to 7 million, and by 2050 it could reach 14 million

The costs of caring for Alzheimer’s patients is also increasing, estimated at $203 billion in 2013, and $1.2 trillion by 2050,  including a 500% increase in combined Medicare and Medicaid spending.

Clearly, finding that major therapeutic breakthrough is crucial, and had been identified as a priority by the Obama Administration.

The first barrier to starting any clinical trial is accurate case ascertainment – we have to be able to correctly identify early Alzheimer’s patients for new experimental treatments.

So far, 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:

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.

With more research trials and potential new effective 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.

New positron emission tomography (PET) technology can actually quantify the amount of amyloid in affected patients’ brains.  A recently published small study showed a very high correlation between amyloid identified on PET scans and amyloid plaque demonstrated in brain biopsy specimens taken from demented patients.

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These tests are going to be very important for research studies.

However, don’t rush to your private doctor’s office asking to have one done just yet!

Although approved by the FDA, these test are not yet covered by Medicare or other insurance covering, and cost between $1500 and $3000.

Furthermore, these are new tests, and their role in clinical neurology practice in still unclear.

Some of these issues were recently clarified in a report by the Amyloid Imaging Taskforce convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging:

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This taskforce concluded that a Amyloid PET scan is indicated for:

Progressive memory impairment or dementia with atypical features, where a positive PET would indicate definite Alzheimer’s, and a negative scan would rule it out and lead to further testing for other possible causes.

Younger patients (aged 50-65) with suspected Alzheimer’s, in whom making a definitive diagnosis is crucial for log term planning and future medical decision making.

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The taskforce concluded that a Amyloid PET scan is unnecessary and/or unhelpful for:

Patients with typical Alzheimer’s disease,

Determining the severity of dementia,

Asymptomatic patients with a family history of dementia or positive apolipoprotein E4 status,

Patients who complain of memory loss but have no objective findings,

Testing purely for medico-legal, disability, insurance or employment related issues.

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Find out more:

Click here to find out more about Memory loss, Mild Cognitive Impairment and Alzheimer’s.

Click here to find out more about diagnosing Alzheimer’s.

Links to the Alzheimer’s Association, Alzheimer’s Foundation of America and CDC Healthy Brain Initiative

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.

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.