Early detection of Alzheimer’s

Early detection of Alzheimer’s disease and current diagnostic and treatment modalities

With increasing life expectancy across the world, the number of elderly people at risk of developing dementia is growing rapidly. The prevalence of dementia rises steeply with age, doubling every 5 years from the age of 60, so that more than one-third of individuals over the age of 80 years of age are likely to develop a dementia.  Alzheimer’s disease remains the most common cause of dementia in all age groups.  AD is a slowly progressive neurodegenerative brain disorder that according to several imaging and neuropsychological studies, has a prodromal stage that can be traced back to 10 to 15 years prior to presentation of the symptoms.   AD is characterized by the presence of amyloid deposition and neurofibrillay tangles together with the loss of cortical neurons and synapses.  Post mortem studies suggest that temporal lobes are the first brain areas that are affected.  The cognitive deficits that are associated with AD become evident and gradually worsen years later. The combination of aging population and the promise, possibly in the near future, of disease-modifying therapies have made the characterization of the early stages of AD a topic of major research interest. The transitional stage between normal memory and dementia is called Mild Cognitive Impairment (MCI).  Although it has been difficult to develop robust and applicable criteria for MCI, it is generally agreed that it is a pre-dementia state that in majority of cases it evolves to a full blown dementia within five years from the diagnosis. In this stage there are memory lapses with preserved function.  Research has suggested that the early detection and treatment of AD provides symptomatic treatment and better quality of life, though does not prolong survival. For many patients the quality of life is important since the disease progresses slowly.  So the search for ideal marker or imaging indicator is underway.  For the early detection of AD, an ideal diagnostic tool must be sensitive to the earliest cognitive or biological changes that are found in AD but should be able to differentiate among early AD, normal aging, other organic brain disorders that cause memory loss and, importantly mimics of early dementia including depression.

Current research into ways for early detection of AD include; neuropsychological testing, structural imaging methods including; PIB ( Pittsburgh Compound B) a radioactive tracer that detects amyloid deposits in the brain of patients in pre-dementia stage, MRI, SPECT, PET and functional MRI. Other laboratory tests include blood and cerebrospinal fluid (CSF) levels of amyloid which seem to correlate with the presence of dementia, though can’t determine the stage of the disease. The Familial form of AD can be tested with genetic studies of APP (Amyloid Precursor Protein), PS1, PS2 genes.  Other genetic testing includes APO E4, which is only a succeptility gene. We must keep in mind; even positive results do not always translate into AD development, and may cause a whole host of medical-legal issues.  For example the future enrollment for health and long term insurance, employment and the stress that may cause within the family.  Since there is no cure, and no perfect treatment, routine screening after a certain age is not fully supported by health care professionals.

Currently we have two classes of drugs for the treatment of AD. The first class is the cholinesterase inhibitors that includes; Aricept, Exelon, and Razadyne.  These drugs inhibit the cholinesterase enzyme and increases the availability of acetylcholine, the hormone that is deficient in patients with AD. The other is Namenda an NMDA receptor antagonist that controls the toxic effect of excitatory neurotransmitter glutamate.  There has been numerous drugs that have been tested and are currently under investigation with disease modifying properties. These new classes of drugs mainly work in the mitochondrial level to prolong cell survival and prevent premature cell death.  There is also IVIG passive immunity vaccine that is currently under investigation with promising results.

Considerable progress has been made in recent years, in both the characterization of the cognitive profile of early AD and its neural basis. Much more work is still required, however, to clarify with greater accuracy and precision the transitional zone between healthy aging and the first manifestation of AD.  At present, it is clear that individuals in the prodromal stages of AD can show marked impairments on formal memory tests, although they continue to cope independently in their normal daily routine, and that this state can persist for several years before dementia develops. Reliably distinguishing such individuals from those in whom mild cognitive deficits will remain stable over time is an important challenge for ongoing research. At this point a purely objective marker would be advantages. Present evidence suggests that no single marker of MRI atrophy or even PET metabolic changes is likely to achieve perfect discriminant value for individual subjects at this prodromal stage on a single scan.  Serial studies over time are needed to identify the volume loss and structural changes. Future work focused on novel, disease- specific, MRI sequences or PET-SPECT radioligands might offer greater predictive value.

M. Reza Bolouri, M.D.