Alzheimer’s Disease: Early diagnosis (Part IV)

Alzheimer’s Disease: Early Diagnosis-Part VI

(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.