I was wondering why measurements of l-dopa levels in the blood do not
reliably predict the response of the patient (whether the patient is well
controlled or experiencing akinesia or dyskinesia), and whether
measurements of dopamine metabolite levels in the blood could be
used to diagnose Parkinson's disease. . In response to this query,
a friend PhD neurobiologist says:
Hi Michel. I finally got the act together. I hope this is useful.
Hugs - Shira
The following difficulties arise in attempts to match the antiparkinson and
dyskinesia-inducing effects of l-dopa to blood levels of l-dopa:
1) Blood levels of l-dopa do not always accurately reflect the
concentration of l-dopa in the brain. L-dopa cannot diffuse freely into
the brain from the blood, but, instead, enters the brain only with the help
of active transport molecules. The transport molecules that move l-dopa
into the brain are the same molecules that normally transport amino acid
nutrients from the blood to the brain. Thus, when the blood concentration
of amino acids is high (such as after a protein-containing meal) the amino
acids will compete with l-dopa for access into the brain, and,
consequently, less l-dopa will enter the brain.
2) While "Off" periods (akinesia) most often occur during times when
brain l-dopa levels are lowest, this is not always the case. Sometimes
they occur as l-dopa levels are falling, but still at levels which are
often sufficient to control akinesia in that patient. It has been
postulated that this type of "Off" period is the result of a transient
desensitization of the dopamine receptor.
3) Short lasting "freezing" which occurs when an otherwise "On"
patient encounters certain situations, such as initiating movement,
turning, arriving at destination, crossing doorways or entering open
walkways is aggravated by increasing l-dopa levels, and is lessened by
lowering the l-dopa dose. The mechanism underlying this paradoxical "On"
freezing is unknown.
4) In some patients dyskinesias occur only when plasma and brain
levels of l-dopa are highest. In this case, lowering the l-dopa dose would
reduce the dyskinesia (but in some would result in incomplete control of
akinesia). In other patients, dyskinesias may occur shortly after the
l-dopa dose is taken, when l-dopa levels are rising in the brain, and also
at the end of the dosage period, as l-dopa levels decline, and are actually
absent in the middle of the dosage period when the l-dopa level is at its
peak. In these patients, taking additional l-dopa will actually stop the
dyskinesia. However, the system appears to adjust to the higher l-dopa
dose, and higher and higher l-dopa dosages are required to prevent the
dyskinesias. If the l-dopa dose is raised too high, this too will produce
dyskinesias. In a third group of patients, dyskinesias are present
throughout the l-dopa dosage period regardless of the concentration of
l-dopa in the blood or the brain.
The precise mechanism underlying the development and expression of
dyskinesias is not known. It has been suggested that the dyskinesia may
reflect a supersensitivity of dopamine receptors or of the intracellular
biochemical mechanisms which mediate the response to receptor stimulation.
There are several different types of dopamine receptor and many many
different intracellular mechanisms that mediate the receptor responses.
The complicated relationship of dyskinesias to l-dopa levels might reflect
different receptor types and mechanisms responding in different manners and
at different rates to fluctuating levels of dopamine. Some receptor types
and post receptor mechanisms may become supersensitized, while others
become desensitized. There is evidence to suggest that the antiparkinson
effects and dyskinesia producing effects of l-dopa are mediated through
different populations of dopamine receptors that respond differently to
fluctuating levels of l-dopa.
******The complicated relationship between l-dopa blood levels and clinical
response should NOT be taken to suggest that maintaining constant blood
levels of l-dopa is unimportant. In fact, there is strong evidence to
suggest that that the repeated large fluctuations in blood and brain l-dopa
levels that occur during typical l-dopa therapy are a major contributing
factor to the development of receptor supersensitivity and dyskinesias.
Much current research is aimed at finding mechanisms of l-dopa delivery
that can result in more constant l-dopa blood and brain levels, and at
finding effective drugs which have a longer plasma half life and which
diffuse easily into the brain.
