How Alzheimer's Gets Diagnosed
Although Alzheimer's disease has been known about for over a century, it wasn't until 1984 that the first diagnostic criteria were formally established. These criteria specifically said that the diagnosis could not be made by laboratory tests. Instead, the diagnosis was to be made clinically, meaning that a doctor used the physical exam and story told by the patient in order to tell if someone had the disease or not.
It is thought that the loss of memory associated with Alzheimer's disease actually occurs relatively late in the disease process. In Alzheimer's disease, abnormally folded proteins build up in the brain, including beta amyloid plaques and neurofibrillary tangles of tau protein. At the same time, the brain begins to shrink (atrophy), in a typical fashion. The hippocampus, which is responsible for many aspects of memory formation, shrinks more than the rest of the brain. This process begins several years before memory problems ever develop.
In 2011, the diagnosis of dementia was changed to reflect new tests that had been discovered in the intervening years. Those tests included magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) studies, and positron emission tomography (PET) techniques. Abnormal findings on these tests are called biomarkers of a disease, meaning a scientific measurement indicating the disease is present. With these techniques, we can now diagnose the underlying disease process of Alzheimer's even before symptoms begin.
Magnetic Resonance Imaging in Alzheimer's Disease
Magnetic resonance imaging takes very good pictures of the inside of the brain. These pictures can help investigate whether other causes of cognitive problems are present in someone suspected to have a dementia, and can also investigate patterns of atrophy to better determine the risk and type of dementia. The hippocampus is typically shrunken (atrophied) in Alzheimer's, and hippocampal volume can help predict the chance of someone with mild cognitive impairment developing dementia.
The hippocampal atrophy may also be present in some other forms of dementia, including frontotemporal dementia, though very specialized and accurate techniques demonstrate a different pattern of atrophy. These techniques are research tools, however, and cannot be applied to an individual patient.
There are atypical forms of Alzheimer's disease, especially in younger people, that do not impact the hippocampus as much as other regions of the brain. An example is posterior cortical atrophy, in which the back part of the brain, responsible for vision, deteriorates. The result are visual problems despite the eyes being completely normal. MRI may still be useful here, though, in detecting atrophy of the back of the brain.
MRI does not use radiation, but involves a strong magnet that could pose danger to people with metal in their body, including cardiac pacemakers.
Cerebrospinal Fluid in Alzheimer's Disease
The brain floats in protective cerebrospinal fluid that then descends down the spinal column. When something is wrong with the brain, sometimes clues can be found in this fluid. A lumbar puncture can be used to draw fluid and test for abnormal biomarkers.
There are three main measurements currently used in cerebrospinal fluid: beta-amyloid 42, total tau, and phosophorylated tau (P-tau).
Beta-amyloid 42 is a form of amyloid deposited in Alzheimer's disease. As the deposits increase on the brain, levels of the protein in the CSF gradually fall. Low amounts of amyloid in the CSF, then, are an index of Alzheimer's disease.
Tau is another misfolded protein in Alzheimer's disease. Unlike amyloid, CSF levels of tau increase as the disease progresses. Phospho-tau may be more specific to neurodegeneration than total tau, which can be elevated by many things that damage brain tissue.
Doctors are still working out the best point to say that a level of tau or amyloid is strongly indicative of Alzheimer's. Other diseases can change levels of these proteins, though not so much as Alzheimer's.
Occasionally a lumbar puncture may be used to exclude other causes of cognitive impairment, such as infections. Although the procedure is generally safe, it is uncomfortable and not without some risk.
PET Scans in Alzheimer's Disease
There are two types of PET scans used in Alzheimer's disease. Fluorodeoxyglucose (FDG) PET measures brain activity, and suggests abnormal patterns of behavior. Amyloid imaging techniques such as PiB or florbetapir address the question of whether there are abnormal protein deposits in the brain.
For example, an FDG PET may correlate with the degree of cognitive impairment someone is suffering. The pattern can suggest an underlying disease process such as Alzheimer's disease, but cannot say that amyloid is present. FDG-PET can be used, for example, to distinguish between a frontotemporal dementia syndrome and Alzheimer's disease.
An amyloid scan cannot say anything about the degree of cognitive impairment, but can say if the protein is present. It may seem surprising that someone's memory ability has little relation with the amount of amyloid in the brain. Reasons for this are uncertain, but likely relate to what is known as cognitive reserve, a brain's ability to work around areas of deficit. This is thought to be increased in patients with very healthy brains, especially if they have a higher degree of education. It is very rare, though, for a scan to be positive in someone under the age of 60 unless they will go on to develop Alzheimer's disease.
Florbetapir has been approved by the Food and Drug Administration for use in adults with cognitive impairment who are being evaluated for Alzheimer's disease, though many think that the impact on patient outcome is too low to justify Medicare reimbursement.
PET scans involve some radiation, which can increase someone's chances of developing cancer. Cancer takes several years to develop, though, and so the risk is lower in older than in younger people.
It is important to recognize that not all people with these brain changes have dementia. In fact they may never get dementia, though the chances are certainly greater. The tests are likely better used together than individually, and were intended to bolster more established techniques, not replace them. In fact, these tests are usually unnecessary to make the diagnosis. If used at all, these newer technologies need to be used in conjunction with a clinical examination and neuropsychological testing in order to better make a diagnosis of Alzheimer's disease.
Sources:
GM McKhann, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984). "Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease". Neurology 34 (7): 939–44
GM McKhann, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-269.
G Rabinovici, Alzheimer's Disease Biomarkers in Clinical Practice. In: American Academy of Neurology Annual Meeting; 2013 March 18; San Diego, California, 2012
It is thought that the loss of memory associated with Alzheimer's disease actually occurs relatively late in the disease process. In Alzheimer's disease, abnormally folded proteins build up in the brain, including beta amyloid plaques and neurofibrillary tangles of tau protein. At the same time, the brain begins to shrink (atrophy), in a typical fashion. The hippocampus, which is responsible for many aspects of memory formation, shrinks more than the rest of the brain. This process begins several years before memory problems ever develop.
In 2011, the diagnosis of dementia was changed to reflect new tests that had been discovered in the intervening years. Those tests included magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) studies, and positron emission tomography (PET) techniques. Abnormal findings on these tests are called biomarkers of a disease, meaning a scientific measurement indicating the disease is present. With these techniques, we can now diagnose the underlying disease process of Alzheimer's even before symptoms begin.
Magnetic Resonance Imaging in Alzheimer's Disease
Magnetic resonance imaging takes very good pictures of the inside of the brain. These pictures can help investigate whether other causes of cognitive problems are present in someone suspected to have a dementia, and can also investigate patterns of atrophy to better determine the risk and type of dementia. The hippocampus is typically shrunken (atrophied) in Alzheimer's, and hippocampal volume can help predict the chance of someone with mild cognitive impairment developing dementia.
The hippocampal atrophy may also be present in some other forms of dementia, including frontotemporal dementia, though very specialized and accurate techniques demonstrate a different pattern of atrophy. These techniques are research tools, however, and cannot be applied to an individual patient.
There are atypical forms of Alzheimer's disease, especially in younger people, that do not impact the hippocampus as much as other regions of the brain. An example is posterior cortical atrophy, in which the back part of the brain, responsible for vision, deteriorates. The result are visual problems despite the eyes being completely normal. MRI may still be useful here, though, in detecting atrophy of the back of the brain.
MRI does not use radiation, but involves a strong magnet that could pose danger to people with metal in their body, including cardiac pacemakers.
Cerebrospinal Fluid in Alzheimer's Disease
The brain floats in protective cerebrospinal fluid that then descends down the spinal column. When something is wrong with the brain, sometimes clues can be found in this fluid. A lumbar puncture can be used to draw fluid and test for abnormal biomarkers.
There are three main measurements currently used in cerebrospinal fluid: beta-amyloid 42, total tau, and phosophorylated tau (P-tau).
Beta-amyloid 42 is a form of amyloid deposited in Alzheimer's disease. As the deposits increase on the brain, levels of the protein in the CSF gradually fall. Low amounts of amyloid in the CSF, then, are an index of Alzheimer's disease.
Tau is another misfolded protein in Alzheimer's disease. Unlike amyloid, CSF levels of tau increase as the disease progresses. Phospho-tau may be more specific to neurodegeneration than total tau, which can be elevated by many things that damage brain tissue.
Doctors are still working out the best point to say that a level of tau or amyloid is strongly indicative of Alzheimer's. Other diseases can change levels of these proteins, though not so much as Alzheimer's.
Occasionally a lumbar puncture may be used to exclude other causes of cognitive impairment, such as infections. Although the procedure is generally safe, it is uncomfortable and not without some risk.
PET Scans in Alzheimer's Disease
There are two types of PET scans used in Alzheimer's disease. Fluorodeoxyglucose (FDG) PET measures brain activity, and suggests abnormal patterns of behavior. Amyloid imaging techniques such as PiB or florbetapir address the question of whether there are abnormal protein deposits in the brain.
For example, an FDG PET may correlate with the degree of cognitive impairment someone is suffering. The pattern can suggest an underlying disease process such as Alzheimer's disease, but cannot say that amyloid is present. FDG-PET can be used, for example, to distinguish between a frontotemporal dementia syndrome and Alzheimer's disease.
An amyloid scan cannot say anything about the degree of cognitive impairment, but can say if the protein is present. It may seem surprising that someone's memory ability has little relation with the amount of amyloid in the brain. Reasons for this are uncertain, but likely relate to what is known as cognitive reserve, a brain's ability to work around areas of deficit. This is thought to be increased in patients with very healthy brains, especially if they have a higher degree of education. It is very rare, though, for a scan to be positive in someone under the age of 60 unless they will go on to develop Alzheimer's disease.
Florbetapir has been approved by the Food and Drug Administration for use in adults with cognitive impairment who are being evaluated for Alzheimer's disease, though many think that the impact on patient outcome is too low to justify Medicare reimbursement.
PET scans involve some radiation, which can increase someone's chances of developing cancer. Cancer takes several years to develop, though, and so the risk is lower in older than in younger people.
It is important to recognize that not all people with these brain changes have dementia. In fact they may never get dementia, though the chances are certainly greater. The tests are likely better used together than individually, and were intended to bolster more established techniques, not replace them. In fact, these tests are usually unnecessary to make the diagnosis. If used at all, these newer technologies need to be used in conjunction with a clinical examination and neuropsychological testing in order to better make a diagnosis of Alzheimer's disease.
Sources:
GM McKhann, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984). "Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease". Neurology 34 (7): 939–44
GM McKhann, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-269.
G Rabinovici, Alzheimer's Disease Biomarkers in Clinical Practice. In: American Academy of Neurology Annual Meeting; 2013 March 18; San Diego, California, 2012
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