Alzheimer’s Disease: Early diagnosis (Part IV)

Alzheimer’s Disease: Early Diagnosis-Part VI

(3/14/17)- Annual healthcare spending on Alzheimer's in the U.S. stands at $259 billion, according to a yearly status report from the Alzheimer's Association.

Caregiver contributions are valued at an additional (unpaid) $230 billion. The total number of people in the U.S. afflicted with the disease is estimated to be at 5.5 million.

(11/11/15)- Dr. John Hardy was honored Sunday evening as one of the $3 million winners in the Breakthrough Prize award dinner at the NASA Ames Research Center in Mountain View, California. A total of $21.9 million was awarded to the winners in the form of seven $3 million winners, one of them being split among 1,300 physicists and $500,000 split among 8 early-career physicists, and $400,000 to a high school student who created a video about Albert Einstein’s theory of relativity.

Dr. Hardy had been contacted by a woman who lived in Nottingham, England at University College London to see if his team would be interested in studying her family’s medical history, since they had suffered from Alzheimer’s’ disease for three generations.

Dr. Hardy and his team’s investigation led to the discovery of a gene mutation that, if inherited always led to the disease.

That gene is presenlin, and its protein is the amyloid precursor protein.

Certain social and personal activities in mid- or late life might help protect against dementia, suggests an observational study in Neurology.

At a median age of 87, about 250 cognitively normal adults reported their current and former activities, demographics, and other risk factors. Roughly 4 years later, nearly half had developed mild cognitive impairment. Cognitive impairment was about 75% less likely in those who had reported both midlife and late-life engagement in artistic activities, and about half as likely in those reporting engagement in social activities or crafts.

Late-life computer use was also associated with a 50% lower risk.

(11/30/12)- Up to 20 percent of patients diagnosed with AD turn out not to have had AD on autopsy, while up to 40 percent of patients diagnosed with other causes of dementia have evidence of AD at autopsy.(Accessed on line Nov. 29th, 2012. Science News, Science Daily. Amyloid Imaging Helps in Evaluating Possible Alzheimer's disease.

Biomarkers for Alzheimer's diseaseYoung adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and Cerebrospinal fluid (CSF) and plasma biomarker findings consistent with AI3 1-42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. (See: The Lancet Neurology, Volume 11, Issue 12, Pages 1048 - 1056, December 2012)

(4/18/12)- The Food and Drug Administration approved a test that has been developed by Eli Lilly & Co. that detects the presence of proteins in the brain that some medical experts feel is related to Alzheimer's disease. If successful, the test could enable clinicians to detect AD earlier and more accurately in patients at the earliest sign of memory problems.

The test uses a chemical called florbetapir, known by the brand name Amyvid that can adhere to clumps of amyloid plaques, which some scientists feel is a key element in the Alzheimer's disease mystery. The chemical is a radioactive substance so it can be followed closely using a brain imaging technique known as positron emission tomography (PET scan).

Florbetapir costs $1,600 per dose. Daniel Skovronsky developed the agent and is the global brand development leader for Amyvid at Lilly. Amyvid will be available in limited quantity starting in June.

The FDA had previously rejected the test in March, last year, saying the company needed to establish a program to train doctors to interpret accurately the scan results.

(8/29/11)- Pat Summit, the winningest coach in Division I women's basketball history at the University of Tennessee announced that she has been diagnosed with early stage Alzheimer's Disease. Ms. Summit, who is 59 years of age, said that she had begun to show signs of memory problems last season, which led her to seek an evaluation at the Mayo Clinic in Minnesota.

Her teams have amassed 1,079 victories and they have won 8 national championships.

According to the Alzheimer's Association, more than 5 million people in the United States have the disease. It is the 6^th leading cause of death and there is no cure for the disease. The Association estimates that about 200,000 people under the age of 65 have the affliction.

(4/25/11)- The National Institute on Aging and Alzheimer's Association will release on Tuesday, a new set of guidelines in evaluating and defining the stages of Alzheimer's disease. It is the first revision of the guidelines in 27 years.

The guidelines divide the disease into 3 stages: a stage when dementia has developed, a middle phase in which mild problems are emerging but daily functions can still be performed, and the third stage where changes in the brain are taking place.

Representative Edward J. Markey (Dem.-Mass.) has introduced a bill in Congress that would create specific Medicare cost codes for Alzheimer's diagnosis.

Please keep in mind that the earliest symptom of Alzheimer's dementia is not always memory loss, but could be mood changes, or problems with language, spatial perception or reasoning.

Under stage 1 of the guidelines for Alzheimer's dementia, the individual has at least two symptoms of cognitive behavioral impairment, which could include problems with language, object or face recognition, reasoning abilities and personality changes. The symptoms result in impairment of proper functioning at work or in daily activities.

Under stage 2 of the guidelines, which is called Mild Cognitive Impairment from Alzheimer's, meaning lower performance in one or more cognitive areas- memory, language, attention and visual spatial skills- than is expected for the person's age and educational background.

Stage 3 of the guidelines is called Preclinical Alzheimer's (Before Symptoms Appear), the individual is recommended for research use only for now: Under the guidelines that person would be recommended for biomarker testing, like brain scans or spinal fluid tests to measure levels of proteins like amyloid and tau. It is important to remember that as many as a third of people with amyloid plaques in their brain have not developed Alzheimer's symptoms.

Please note that there is no drug currently approved by the Federal Drug Administration that can prevent or entirely halt the onset of Alzheimer's disease.

(1/27/11)- Even though the Food and Drug Administration (FDA) staff cast a skeptical eye on Eli Lilly & Co.'s Avid Radiopharmaceutical Inc. subsidiary's imaging drug Amyvid for the early detection of Alzheimer's disease in living patients, the FDA panel unanimously approved the drug contingent on radiologists agreeing on what the scans say and doctors being trained in how to read the scans.

The FDA staffers had questioned whether there is any real-world use for such a test in a disease that has no cure. Two staffers had recommended against approval of the drug.

Lilly had purchased Avid last month for an initial payment of $300 million

The key study involving Amyvid that figured in the review involved only 29 patients considered near the end of life. After they died and had their brains examined in an autopsy, 15 were judged to meet the criteria for Alzheimer's disease, and 14 of those had scans that were positive for amyloid before they died.

A large study sponsored in part by the National Institute on Aging is scanning health people and following them to see if the scans predict the risk of developing Alzheimer's disease.

It is estimated that more than 5 million Americans suffer from Alzheimer's disease.

The scientific community is at odds as to whether or not the buildup of amyloid plaque on the brain is the key to Alzheimer's disease.

(8/15/10)- Would you be willing to take a medical test that could predict, with 100% accuracy, whether or not you would develop Alzheimer's disease in your lifetime? Please keep in mind that there is no cure for Alzheimer's disease, only the ability to retard its development for a period of time

Researchers have reported on a study they conducted that showed that a spinal fluid tap could predict whether or not an individual will develop the disease. The results of the study were published in the most recent edition of the Archives of Neurology. Dr. Johhn Trojanowski, a University of Pennsylvania researcher was the senior author of the paper.

One of the major drawbacks is the fact that spinal taps are painful, since the procedure involves inserting a needle in the spinal space and withdrawing a small amount of fluid. The study included more than 300 patients in their 70s.One hundred fourteen of the patients had normal memories; 200 had memory problems and 102 of them had been diagnosed with

Their spinal fluid was analyzed for amyloid beta, a protein fragment that forms plaques in the brain, and for tau, a protein that accumulates in dead and dying nerve cells in the brain.

The study was a double blind study, and the subjects were not told what the tests showed. Almost all of the patients with AD had characteristic spinal fluid protein levels

Nearly three quarters of people with mild cognitive impairment had AD-like spinal fluid proteins, and it turned out, developed AD within 5 years

About one third of the subjects with normal memories had spinal fluid indicating that they would develop Alzheimer's within the next few years. A great deal more study has to be done before this test will gain widespread usage. There are presently several commercial spinal taps available but no one need rush out and take the test tomorrow.

(4/21/10)- There is no definitive test today to determine if an individual has Alzheimer's Disease. As a matter of fact, it is only after death, can an autopsy of the deceased's brain determine that the individual had AD.

There are several companies trying to develop tests to determine the likelihood that AD has begun in individuals, rather than through clinical assessment of the patient's memory and cognitive functions. It is estimated that there are about 5.1 million Americans who presently suffer from the disease.

Many in the scientific community believe that the buildup of amyloid plaques, a sticky substance that has been found in between the brain cells either causes or contributes to the disease. On the other hand, many scientists do not believe that this is the case.

The chemical imaging compounds being developed to determine if a patient has AD adheres to amyloid plaque, and so the theory goes, when medical imaging equipment shows the coloring signs of these compounds in the brain, it would be a strong indication that AD is present.

Avid Radiopharmaceuticals Inc., based in Philadelphia presented preliminary data from a late-stage clinical trial showing that the company's compound, called florbetapir, binds to the amyloid plaque in the brain and correctly identified which patients had the disease.

The results of Avid's Phase III trial were presented at the recent American Academy of Neurology conference in Toronto. Bayer AG, which has a molecule called florbetaben, licensed from Avid, is also in a late-stage development trial. Results of the trial are expected in 2011.

(10/27/08)-A biomarker is a term for something present in the body which can indicate disease, such as a certain protein or molecule. The Nottingham team will be identifying biomarkers by looking at proteins in the blood of Alzheimer's patients compared to a control group of healthy older people.

The researchers at The University of Nottingham hit upon the idea of using biomarkers as a means of diagnosis and will be involved in collecting the samples in conjunction with collaborators in the UK and EU, while the samples will be tested using technology based at Nottingham Trent University

The Medical Research Council (MRC) Cognitive Function and Ageing Study (CFAS) is a large UK-based longitudinal multicoated study looking at the health and cognitive function of older people. The study started in the late 1980s with the initial aim of investigating dementia and cognitive decline in a representative sample of more than 18,000 people aged over 65 years.

Researchers from Nottingham's two universities are joining forces to develop a simple blood test to diagnose Alzheimer's disease. The £200,000 study, funded by the leading charity the Alzheimer's Research Trust, will aim to find out whether 'biomarkers' in blood could be used to identify someone with Alzheimer's.

CFAS investigated a number of potential risk factors for dementia. Data on these risk factors was collected at the first interviews with participants (baseline). Any association with the development of dementia in the population was analyzed after 2 years and 6 years. (a nested case-control analysis of a population-based cohort study)

Findings

The study found that female sex and particularly increasing age were more strongly associated with dementia
More years of education were associated with lower levels of dementia.
Poor self-perceived health increased the risk for incident dementia
Alcohol and smoking (never, past and current) were neither strongly protective nor predictive.
Stroke was strongly related to incident dementia as was Parkinson’s disease
Exposure to general anesthesia (GA) was inversely associated with dementia development with a trend with increasing GA exposure.
The median survival time for persons aged 65 years and older who developed incident dementia is 4.5 years from onset.
The significant factors that predicted mortality in the presence of dementia include sex, age of onset and disability.
Survival among those with dementia who were between ages of 65 and 69 at onset was 10.7 years, compared with 3.8 years for those aged 90 years and older.

(This information was published online before print Jan. 10, 2008: BJM)

(Feb 12, 2007)- A recently completed 1.1 million dollar National Institute of Health National Institute on Aging study that lasted three years concluded that early Alzheimer’s could be diagnosed with a high degree of accuracy by evaluating EEG signals. A study like this may lead to earlier diagnosis and therefore earlier treatment and improved quality of life for people at the earliest stages of the disease.

The lead researchers for the study were Drs. Robi Polikar (an electrical and computer engineer), Christopher Clark and John Kounis. They wrote in one of their collaborative research papers:

"a need to find an accurate, inexpensive and non-intrusive procedure that can be made available to community healthcare providers for early diagnosis of Alzheimer's disease is becoming more and more urgent as a major health concern. Several recent studies have looked at analyzing electroencephalogram signals through the use of wavelets and neural networks. In this study, multiresolution wavelet analysis, coupled with the ensemble of classifiers based boosting algorithm is used on the P300 component of the event related potentials (ERP) to determine the feasibility of the approach as a diagnostic tool for early diagnosis of AD."

This study is a good example of translational medicine, where different disciples work as a unit to develop medical instruments to enhance the quality of life.

Prior studies have indicated that AD has a long pre-clinical period in which there may be some cognitive impairment, more noticeable in poorly educated individuals and not diagnosable as AD in its earliest stages. This seems especially true for the highly educated whose Alzheimer’s disease may not manifest itself at the mild stage of the disease. The more educated individuals may have an intellectual reservoir that masks the identity of the disease. This also may play a part in the popular idea that exercising the brain may stave off dementia. Individuals who do these exercises tend to be better educated and appear to have the intellectual reservoir that can mask the disease, so that it only breaks through at a more severe stage of the disease.

A study that appeared in the April 17, 2007 issue of Neurology indicated that people who develop dementia of the Alzheimer type experience brain structure changes years before any signs of memory loss begin. Dr. Charles Smith, director of the University of Kentucky Magnetic Resonance Imaging and Spectroscopy Center was the principle investigator among a host of researchers. The objective was to show that alterations of brain structurein normal aged individuals precede the development of mild cognitiveimpairment (MCI) or Alzheimer disease (AD). The study results confirmed their objective, indicating that "Initially normal subjects who eventually developedMCI demonstrated decreased gray matter volumes in the anteromedialtemporal lobes bilaterally and left angular gyrus while stillcognitively normal".This led the researchers toconclude that "structural brain changes in anatomic areas involvedin higher cognitive processes precede clinical signs and symptomsin longitudinally followed normal subjects destined to developmild cognitive impairment". Dr. Smith is quoted as saying; "We found that changes in the brain structured are present in clinically normal people on average of 4 years before mild cognitive impairment (MCI) diagnosis… We know that people with MCI or AD have less brain volume, but before now we didn’t know if these brain structure changes existed, and to what degree, before memory loss begins."

Dr. Smith’s study lasted 5 years. The study population consisted of 136 persons over the age of 65 who exhibited no neurological or mental status testing signs of cognitive problems. At the end of the study, 23 people had developed MCI and 9 of these 23 had gone on to develop Alzheimer’s disease. Extrapolating these figures to a general population would indicate that approximately 16% of the population over 65 will develop some form of cognitive impairment in 5 years and that 6 % will develop AD, suggestive of the extent of this problem for society.

In general, brain scans are an expensive proposition and the machine is not generally available. This is where Drs. Polikar, Clark and Kounis study of EEG signals may prove a valuable tool to diagnose dementia at a very early stage. EEG is non-evasive, simple to do, can be repeated when necessary and can be done in a physician’s office.

It is a well known axiom that the earlier you identify the onset of a disease, the easier it is to treat. Ideally, it would be more practical to prevent the disease from developing. This is where vaccines play an essential part in eradicating a disease. Presently, there are pharmaceutical companies exploring these roads, with success teasingly close but not yet on the mark.

The early identification of the onset of the disease may provide the clues necessary to prevent the full-blown development of the disease and might help in the discovery of novel therapeutic targets for Alzheimer’s disease. The full story is yet to come.

(2/14/04)- Scientists at the University of Pittsburgh have developed a compound-called Pittsburgh Compound B, that, in the brain can attach itself to the protein beta-amyloid, or amyloid plaque, which is suspected to be involved with Alzheimer's disease. The compound is a radioactive dye thatis injected into the patient. Researchers were able to locate and quantify amyloid plaques in the brain using a PET scan.

"This is the first study to reliably detect any amyloid deposits in the brains of living subjects, " says lead author Willian E. Klunk, associate professor of psychiatry at the University of Pittsburgh School of Medicine. The study was published in the journal of Neurlogy.

Earlier this year a Medicare advisory panel recommended against approving positron emission tomography (PET) scans for use in diagnosing Alzheimer's disease. According to Medicare, more studies need to be done to prove that a PET scan can accurately predict the onset of Alzheimer's disease. Medical- imaging companies are back in Washington battling this decision. Many medical experts are concerned that if too many hospitals and clinics install PET systems, the physicians affiliated with them will come under financial pressure to order them. It is feared that the overordering of these tests will take place in questionable situations.

A study group led by Dan Silverman, assistant professor of molecular and medical pharmacology at the University of California, Los Angeles concluded that PET scans do cut unnecessary drug therapy and nursing home care costs. Full PET scans cost between $2,000 to $3,000, while those on the brain alone, used to diagnose Alzheimer's disease, cost about $1,000. Dr. Silverman's study group concluded that those who are diagnosed early enough with Alzheimer's can be treated with drug therapy that will slow the progression of the disease, and thus delay by nine months or more the more costly stay in a nursing home.

For every 100 patients suffering from early cognitive decline, conventional methods would have falsely attributed the patients' symptoms to early Alzheimer's in 23 cases, and overlooked eight cases of the disease. Using a benefit risk analysis the study concluded that the PET scan would have prevented 11 of the 23 false positives and five of the eight negatives. The results of the study were published in the Journal of Molecular Imaging and Biology.

Mental decline with aging is probably of a heterogeneous origin, manifesting itself as a symptom in many diseases as well as a normal process of aging. Any method that could identify the decline at an early stage, and pinpoint the pathology would allow for greater benefit in the treatment process. Since we appear to have some drug therapies (Aricept, Tacrine) which slow cognitive decline progression on Alzheimer’s disease, it follows that these therapies may prove more effective if used early on in the disease.

Thus the search for early neuroanatomical and pathophysiological signs of the disease continues. At the same time, researchers will have to tease out those who have Alzheimer’s disease from other forms of cognitive decline on a more direct basis. A step in this direction appears to have been made by Dr. Scott A. Small, a neurologist at the Sergievsky Center and Columbia Presbyterian Medical Center, New York, who presented preliminary findings at the annual meeting of the American Academy of Neurology in Toronto.

Dr. Small and his group, using a functional magnetic resonance imaging device, found two distinct patterns within the hippocampus of the brain. Specifically, he studied the entorhinal cortex, finding that nondemeted but with minor cognitive impairment elderly showed functional changes associated with a clinical diagnosis of Alzheimer’s disease.

Could this be the site of the first stages of the disease, still at a subclinical level? The object now is to follow these individuals over a period of time and see if they develop AD and distinguish between those that do and those that do not develop Alzheimer’s disease. The important part of this study is that each individual acts as his/her own control. A base line structural and functional image is established and changes are monitored over time and compared with base line.

Thus, Alzheimer’s disease would appear to typically start in the entorhinal cortex, spread to other parts of the hippocampus and than progress to the temporal cortex, parietal cortex, and frontal cortex. What the functional magnetic resonance imaging does is to provide a better look at smaller parts of the brain as they are being activated providing evidence of the progressive nature of this disease.

There is growing need of evidence that can distinguished Alzheimer’s disease from other dementias because drugs used to treat Alzheimer’s disease may not be effective in treating other dementias—even may worsen the condition. There is no gold standard for diagnosis of Alzheimer’s disease except on autopsy where an accumulation of neurofibrillary tangles and plaque density are found as a distinguishing marker of Alzheimer’s disease. It takes highly skilled professionals to make the diagnosis. It involves using neuropsychological testing and skillful clinical interviewing of the individual and family to establish the type of memory that is functionally impaired and extrapolating a diagnosis from this information.

In the early stages of Alzheimer’s disease both episodic and semantic memory are effected. Episodic memory involves recall of day's events, while semantic memory involves the ability to remember names, words or historical events. Further down the line, working memory (ability to briefly hold information and manipulate it before storing it more permanently) becomes vulnerable leading to difficulty doing checkbooks or driving safely.

Concomitantly, visuospatial skills (sense of direction) deteriorate and the individual becomes disoriented. Interestingly, social behaviors are usually preserved in the early stages of the disease with agitation more significant in later stages of the disease. (Some recent studies are showing the effectiveness of anticonvulsant drugs i. e. carbamazepine, divalproex, neurontin etc., in controlling this symptom as opposed to Haldol, which appears to have a wider range of adverse side effects.

Individual variations in these stages may occur and may be correlated to premorbid personality and the etiology of the disease i. e. early (familial) or late (sporadic) onset. (In the future parts of this series, more information about anticonvulsants will be presented as well as alternative therapies.

Contrast Alzheimer’s disease with frontaltemporal dementias where memory, comprehension and sense of direction are spared, while planning, organizing, or contemplating and achieving a complex series of activities are impaired. Along with evidence of ritualistic compulsive behavior, social withdrawal, apathy and disinhibition and you begin to see how a good diagnostician can make the important diagnostic distinction on basis of indirect evidence. With functional magnetic resonance imaging, direct markers might be found which might make for more objective diagnosis and competent treatment regimens. Research in this area will not show fruition for about five years.