Michele G. Sullivan

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

BARCELONA – Severe hyposmia may be associated with a deficiency of striatal dopamine transporter protein and slight cognitive decline – characteristics that could identify people with an increased risk of developing Parkinson’s disease, according to preliminary findings from the Parkinson’s Associated Risk Study.

"This is an interesting observation: [Cognitive] decline may be occurring well in advance of motor symptoms," Dr. Kenneth Marek said at the International Conference on Alzheimer’s and Parkinson’s Diseases. "This might be something we could use to predict who will develop dopamine transporter deficiency and, eventually, symptomatic Parkinson’s."

The prospective PARS (Parkinson’s Associated Risk Study) aims to test the effectiveness of two biomarkers – sense of smell and dopamine transporter imaging – in identifying subjects who are at risk of developing the disease. First-degree relatives of Parkinson’s disease patients and control subjects will be followed for 2 years to determine whether a deficiency in striatal dopamine transporter (DAT) increases their disease risk.

Dr. Marek and his coinvestigators recruited subjects by a mass mailing of the UPSIT (University of Pennsylvania Smell Identification Test); those scoring in the 15th percentile and lower are invited to participate. So far, 9,400 tests have been mailed out, half to relatives of patients and half to subjects recruited by community notices. About 5,000 have sent the test back.

"We have identified 650 people who were hyposmic below this 15th percentile," said Dr. Marek, president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This is considered rather severe hyposmia and, interestingly, only about a third of these folks noticed that they even had this symptom."

He presented data on 303 participants (203 hyposmic, 100 normosmic) who had undergone the baseline evaluation. Tests included a neuropsychological test battery, early Parkinson’s symptom score, and SPECT (single-photon emission CT) brain imaging of striatal DAT binding with the imaging compound iodine-123–beta-CIT. The study is grouping participants according to their striatal DAT levels: Greater than 80% is considered normal, 65%-80% is considered indeterminate, and less than 65% is considered a deficiency consistent with Parkinson’s disease.

Of the 203 hyposmic subjects, 11% had a DAT level less than 65%, compared with 1% of the normosmic group, a significant difference. "That one person in the normosmic group also has a REM sleep behavior disorder," Dr. Marek noted.

Indeterminate DAT levels were seen in 17% of the hyposmic and in 7% of the normosmic groups, and normal levels were seen in 71% of the hyposmic and 92% of the normosmic groups. (Percentages in the hyposmic group do not equal 100% because of rounding.)

Bowel habits also varied significantly between the groups. Nearly half (48%) of those with the lowest DAT density reported fewer than one bowel movement per day, compared with 21% of the normal-level group. Conversely, 13% of the lowest-level group reported one or more bowel movements per day, compared with 51% of the normal-level group.

"Similarly, [the lowest DAT-level group was] much more likely to endorse questions related to REM sleep behavior disorder," Dr. Marek said. "And when we used another tool – a nine-item symptom rating scale that assesses early Parkinson’s – those individuals in the lowest DAT group were more likely to endorse the symptoms."

Taking these data into account, he said it seems as if "these individuals express a number of features that we might call ‘premotor Parkinsonism.’ "

The researchers have completed cognitive testing on 131 participants (17 with decreased DAT levels and 114 with normal levels). Mean age was the same (68 years) in both groups and their educational levels were not significantly different.

"Even in this group, [in which all the] subjects were entirely cognitively normal, it was possible to distinguish individuals based on their cognitive function related to whether they had this early DAT deficit or not," Dr. Marek said. "I would not call them cognitively impaired, because they were not, but they were different and easily distinguished, based on their scores and imaging outcomes."

Finally, he said, when the global cognitive scores of individuals in all three DAT levels were compared, "we got some sense that there is a relationship between the extent of DAT deficit and the likelihood of seeing these cognitive changes."

The PARS study is being sponsored by the U.S. Department of Defense, the Michael J. Fox Foundation for Parkinson’s Research, and the National Parkinson Foundation. As an employee of the Institute for Neurodegenerative Disorders, Dr. Marek participates in multiple clinical studies, some of which are funded by drug companies.

MADRID – The risk/benefit balance is a tough one when it comes to women who become pregnant while they’re taking antipsychotic medication. Data are sparse on safety during pregnancy and lactation, but there are cases of women with stable mental disorders who rapidly deteriorated after being taken off their medication because of concern about a developing fetus.

In fact, Dr. Jayashri Kulkarni said, a patient with whom she was involved experienced this very thing, and her case was the impetus for creating the National Registry of Antipsychotic Medications in Pregnancy (NRAMP).

"The background of the project is a very sad one," she said, describing the case of a 28-year-old woman with schizophrenia who had "lived a zombielike life" on typical antipsychotics, until she began taking first risperidone and then olanzapine. Her symptoms abated and cognition improved so that she was able to work as a sales assistant. She became involved in a 2-year relationship with a coworker, and then became pregnant.

"Her general physician said there were no safety data on the drug and took her off it," Dr. Kulkarni said. Within 2 weeks, the patient’s auditory hallucinations returned. At 20 weeks’ gestation, she attacked a customer and was fired from her job. At 28 weeks, she was involuntarily admitted after attempting to slash her abdomen in response to the voices’ commands to destroy "the alien" growing in her. At that point, her partner forbade her to return to their apartment.

She was given two older medications – chlorpromazine and then phenytoin (Dilantin) – which were ineffective. "By 32 weeks, she was very drowsy, had excessive salivation [and] upper limb cogwheel rigidity, and was still hearing voices telling her to kill herself and the ‘alien within’ by slashing her abdomen."

At that point, she ran away from the hospital and into traffic, and was struck by a car. She sustained three broken ribs and a pneumothorax, but the fetus was unharmed. More medication trials followed, and were unsuccessful; she often had to be restrained in bed to prevent her from running away again.

At 36 weeks, she delivered a small-for-gestational-age girl, who was managed in the neonatal intensive care unit for a month. After that, the child’s father was granted full custody, and the patient was admitted to a psychiatric hospital with no contact with her infant.

By the time the baby was 5 weeks old, her mother was again stable, this time on aripiprazole. Although her schizophrenia symptoms remitted, she developed postnatal depression. Without legal access to her child, she eventually broke into the father’s home to see the baby. She failed to attend a compulsory psychiatric consult the next week, and committed suicide 2 days later.

"It’s a horrible story and unfortunately, it’s not one that is familiar to many clinicians," Dr. Kulkarni said. "This is what prompted to me to think about how this situation went wrong. It went wrong because we have no way of knowing what is the safest drug to use for both mother and baby."

[Main story: Neonatal Outcomes Worse in Babies Exposed to Antipsychotic]

She conceived the idea of the registry, which was initially funded "with a tiny grant from the Rotary Club."

Funding now comes mainly from Astra-Zeneca, Janssen-Cilag, and Mayne Pharmaceuticals, as well as the Australian Rotary Health Research Fund.

MADRID – The risk/benefit balance is a tough one when it comes to women who become pregnant while they’re taking antipsychotic medication. Data are sparse on safety during pregnancy and lactation, but there are cases of women with stable mental disorders who rapidly deteriorated after being taken off their medication because of concern about a developing fetus.

In fact, Dr. Jayashri Kulkarni said, a patient with whom she was involved experienced this very thing, and her case was the impetus for creating the National Registry of Antipsychotic Medications in Pregnancy (NRAMP).

"The background of the project is a very sad one," she said, describing the case of a 28-year-old woman with schizophrenia who had "lived a zombielike life" on typical antipsychotics, until she began taking first risperidone and then olanzapine. Her symptoms abated and cognition improved so that she was able to work as a sales assistant. She became involved in a 2-year relationship with a coworker, and then became pregnant.

"Her general physician said there were no safety data on the drug and took her off it," Dr. Kulkarni said. Within 2 weeks, the patient’s auditory hallucinations returned. At 20 weeks’ gestation, she attacked a customer and was fired from her job. At 28 weeks, she was involuntarily admitted after attempting to slash her abdomen in response to the voices’ commands to destroy "the alien" growing in her. At that point, her partner forbade her to return to their apartment.

She was given two older medications – chlorpromazine and then phenytoin (Dilantin) – which were ineffective. "By 32 weeks, she was very drowsy, had excessive salivation [and] upper limb cogwheel rigidity, and was still hearing voices telling her to kill herself and the ‘alien within’ by slashing her abdomen."

At that point, she ran away from the hospital and into traffic, and was struck by a car. She sustained three broken ribs and a pneumothorax, but the fetus was unharmed. More medication trials followed, and were unsuccessful; she often had to be restrained in bed to prevent her from running away again.

At 36 weeks, she delivered a small-for-gestational-age girl, who was managed in the neonatal intensive care unit for a month. After that, the child’s father was granted full custody, and the patient was admitted to a psychiatric hospital with no contact with her infant.

By the time the baby was 5 weeks old, her mother was again stable, this time on aripiprazole. Although her schizophrenia symptoms remitted, she developed postnatal depression. Without legal access to her child, she eventually broke into the father’s home to see the baby. She failed to attend a compulsory psychiatric consult the next week, and committed suicide 2 days later.

"It’s a horrible story and unfortunately, it’s not one that is familiar to many clinicians," Dr. Kulkarni said. "This is what prompted to me to think about how this situation went wrong. It went wrong because we have no way of knowing what is the safest drug to use for both mother and baby."

[Main story: Neonatal Outcomes Worse in Babies Exposed to Antipsychotic]

She conceived the idea of the registry, which was initially funded "with a tiny grant from the Rotary Club."

Funding now comes mainly from Astra-Zeneca, Janssen-Cilag, and Mayne Pharmaceuticals, as well as the Australian Rotary Health Research Fund.

MADRID – The risk/benefit balance is a tough one when it comes to women who become pregnant while they’re taking antipsychotic medication. Data are sparse on safety during pregnancy and lactation, but there are cases of women with stable mental disorders who rapidly deteriorated after being taken off their medication because of concern about a developing fetus.

In fact, Dr. Jayashri Kulkarni said, a patient with whom she was involved experienced this very thing, and her case was the impetus for creating the National Registry of Antipsychotic Medications in Pregnancy (NRAMP).

"The background of the project is a very sad one," she said, describing the case of a 28-year-old woman with schizophrenia who had "lived a zombielike life" on typical antipsychotics, until she began taking first risperidone and then olanzapine. Her symptoms abated and cognition improved so that she was able to work as a sales assistant. She became involved in a 2-year relationship with a coworker, and then became pregnant.

"Her general physician said there were no safety data on the drug and took her off it," Dr. Kulkarni said. Within 2 weeks, the patient’s auditory hallucinations returned. At 20 weeks’ gestation, she attacked a customer and was fired from her job. At 28 weeks, she was involuntarily admitted after attempting to slash her abdomen in response to the voices’ commands to destroy "the alien" growing in her. At that point, her partner forbade her to return to their apartment.

She was given two older medications – chlorpromazine and then phenytoin (Dilantin) – which were ineffective. "By 32 weeks, she was very drowsy, had excessive salivation [and] upper limb cogwheel rigidity, and was still hearing voices telling her to kill herself and the ‘alien within’ by slashing her abdomen."

At that point, she ran away from the hospital and into traffic, and was struck by a car. She sustained three broken ribs and a pneumothorax, but the fetus was unharmed. More medication trials followed, and were unsuccessful; she often had to be restrained in bed to prevent her from running away again.

At 36 weeks, she delivered a small-for-gestational-age girl, who was managed in the neonatal intensive care unit for a month. After that, the child’s father was granted full custody, and the patient was admitted to a psychiatric hospital with no contact with her infant.

By the time the baby was 5 weeks old, her mother was again stable, this time on aripiprazole. Although her schizophrenia symptoms remitted, she developed postnatal depression. Without legal access to her child, she eventually broke into the father’s home to see the baby. She failed to attend a compulsory psychiatric consult the next week, and committed suicide 2 days later.

"It’s a horrible story and unfortunately, it’s not one that is familiar to many clinicians," Dr. Kulkarni said. "This is what prompted to me to think about how this situation went wrong. It went wrong because we have no way of knowing what is the safest drug to use for both mother and baby."

[Main story: Neonatal Outcomes Worse in Babies Exposed to Antipsychotic]

She conceived the idea of the registry, which was initially funded "with a tiny grant from the Rotary Club."

Funding now comes mainly from Astra-Zeneca, Janssen-Cilag, and Mayne Pharmaceuticals, as well as the Australian Rotary Health Research Fund.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.

"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."

Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.

He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."

That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.

Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.

"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."

He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."

In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.

After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.

"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."

The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.

While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."

During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.

"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."

Dr. Growdon’s study was sponsored by the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research. He reported no relevant financial disclosures.

BARCELONA – Early neuronal death may spark symptoms that can precede the classic motor dysfunction of Parkinson’s disease by up to 20 years.

Rather than beginning in the substantia nigra and moving into the cerebellar regions, nerve damage may begin in the dorsal motor nucleus of the vagal nerve and progress upward into the midbrain, killing neurons all along its path. Constipation, cardiac denervation, and rapid eye movement sleep disorder are some of the conditions that may appear as the march of cell death continues, Dr. Yoshikuni Mizuno said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"Parkinson’s probably starts in the peripheral portions of the vagal nerve," said Dr. Mizuno, director of the Research Institute for Diseases of Old Age at Juntendo University, Tokyo. "When the neurons die, their content is expelled into the extraneural space in the medulla oblongata." Other nerve terminals pick up this intracellular debris and die as well, expelling their own contents as damage progresses. "Eventually, this reaches the substantia nigra and the higher cerebellar neurons. This, I believe, is the model for the spread of Parkinson’s."

Constipation can be one of the first symptoms, occurring when Lewy body lesions first appear on the vagal nerve’s dorsal motor nucleus. This is generally 15-20 years before the onset of motor symptoms, Dr. Mizuno said.

The Honolulu Heart Program study clearly showed the association between Parkinson’s disease and constipation. The study followed almost 7,000 men. Over an average of 12 years, 96 developed Parkinson’s disease. In a multivariate analysis, men who had fewer than one bowel movement per day were four times more likely to develop the disease than were men with two or more bowel movements per day (Neurology 2001;57:456-62).

"I think most of these patients already had Parkinson’s before the onset of motor symptoms," he said.

As cell death proceeds along the nerve, it can affect cardiac innervation. Cardiac scintigraphy with the imaging agent iodine-123 metaiodobenzylguanidine (MIBG) highlights norepinephrine transport cells in the normal heart. "In patients with Parkinson’s and dementia with Lewy bodies, you don’t see this, because of the loss of postganglionic parasympathetic nerve fibers," Dr. Mizuno said. "In Alzheimer’s, as well as in progressive supranuclear palsy and multisystem atrophy, you do have nice visualization of these fibers, and this is a very useful test for differentiating Lewy body disorders from these other diseases."

His own studies suggest that MIBG cardiac uptake may parallel the progression of Parkinson’s disease. About half of patients with stage 1 disease show reduced uptake, but "there is much more markedly diminished cardiac MIBG uptake in those with stage 2 disease or higher," Dr. Mizuno said.

Disordered sleep can occur when cell damage advances to the pons – about 10 years before motor symptoms are apparent. "Half of the patients with idiopathic REM sleep disorder will go on to develop Parkinson’s disease," he said.

As nerve damage progresses further, the olfactory bulb may be affected. Hyposmia affects most (80%) Parkinson’s patients, but about 40% report a decline in olfactory function before the onset of motor symptoms. "The interval between hyposmia and motor symptom onset is about 5 years," Dr. Mizuno said.

The characteristic motor symptoms appear only when most of the dopaminergic neurons in the substantia nigra have died. If the damage progresses further, the cortex may be affected, leading to dementia.

"If you compare clinical and lab findings in Parkinson’s disease dementia and dementia with Lewy bodies, you will notice a lot of similarities: constipation, loss of smell, executive dysfunction, fluctuating cognition, and visuospatial dysfunction," Dr. Mizuno said. "The only difference between the two is the presentation of initial symptoms. If motor symptoms appear first, we call it Parkinson’s disease, while if dementia is the initial symptom, we call it dementia with Lewy bodies."

Dr. Mizuno declared no potential financial conflicts of interest.

BARCELONA – Early neuronal death may spark symptoms that can precede the classic motor dysfunction of Parkinson’s disease by up to 20 years.

Rather than beginning in the substantia nigra and moving into the cerebellar regions, nerve damage may begin in the dorsal motor nucleus of the vagal nerve and progress upward into the midbrain, killing neurons all along its path. Constipation, cardiac denervation, and rapid eye movement sleep disorder are some of the conditions that may appear as the march of cell death continues, Dr. Yoshikuni Mizuno said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"Parkinson’s probably starts in the peripheral portions of the vagal nerve," said Dr. Mizuno, director of the Research Institute for Diseases of Old Age at Juntendo University, Tokyo. "When the neurons die, their content is expelled into the extraneural space in the medulla oblongata." Other nerve terminals pick up this intracellular debris and die as well, expelling their own contents as damage progresses. "Eventually, this reaches the substantia nigra and the higher cerebellar neurons. This, I believe, is the model for the spread of Parkinson’s."

Constipation can be one of the first symptoms, occurring when Lewy body lesions first appear on the vagal nerve’s dorsal motor nucleus. This is generally 15-20 years before the onset of motor symptoms, Dr. Mizuno said.

The Honolulu Heart Program study clearly showed the association between Parkinson’s disease and constipation. The study followed almost 7,000 men. Over an average of 12 years, 96 developed Parkinson’s disease. In a multivariate analysis, men who had fewer than one bowel movement per day were four times more likely to develop the disease than were men with two or more bowel movements per day (Neurology 2001;57:456-62).

"I think most of these patients already had Parkinson’s before the onset of motor symptoms," he said.

As cell death proceeds along the nerve, it can affect cardiac innervation. Cardiac scintigraphy with the imaging agent iodine-123 metaiodobenzylguanidine (MIBG) highlights norepinephrine transport cells in the normal heart. "In patients with Parkinson’s and dementia with Lewy bodies, you don’t see this, because of the loss of postganglionic parasympathetic nerve fibers," Dr. Mizuno said. "In Alzheimer’s, as well as in progressive supranuclear palsy and multisystem atrophy, you do have nice visualization of these fibers, and this is a very useful test for differentiating Lewy body disorders from these other diseases."

His own studies suggest that MIBG cardiac uptake may parallel the progression of Parkinson’s disease. About half of patients with stage 1 disease show reduced uptake, but "there is much more markedly diminished cardiac MIBG uptake in those with stage 2 disease or higher," Dr. Mizuno said.

Disordered sleep can occur when cell damage advances to the pons – about 10 years before motor symptoms are apparent. "Half of the patients with idiopathic REM sleep disorder will go on to develop Parkinson’s disease," he said.

As nerve damage progresses further, the olfactory bulb may be affected. Hyposmia affects most (80%) Parkinson’s patients, but about 40% report a decline in olfactory function before the onset of motor symptoms. "The interval between hyposmia and motor symptom onset is about 5 years," Dr. Mizuno said.

The characteristic motor symptoms appear only when most of the dopaminergic neurons in the substantia nigra have died. If the damage progresses further, the cortex may be affected, leading to dementia.

"If you compare clinical and lab findings in Parkinson’s disease dementia and dementia with Lewy bodies, you will notice a lot of similarities: constipation, loss of smell, executive dysfunction, fluctuating cognition, and visuospatial dysfunction," Dr. Mizuno said. "The only difference between the two is the presentation of initial symptoms. If motor symptoms appear first, we call it Parkinson’s disease, while if dementia is the initial symptom, we call it dementia with Lewy bodies."

Dr. Mizuno declared no potential financial conflicts of interest.

BARCELONA – Early neuronal death may spark symptoms that can precede the classic motor dysfunction of Parkinson’s disease by up to 20 years.

Rather than beginning in the substantia nigra and moving into the cerebellar regions, nerve damage may begin in the dorsal motor nucleus of the vagal nerve and progress upward into the midbrain, killing neurons all along its path. Constipation, cardiac denervation, and rapid eye movement sleep disorder are some of the conditions that may appear as the march of cell death continues, Dr. Yoshikuni Mizuno said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"Parkinson’s probably starts in the peripheral portions of the vagal nerve," said Dr. Mizuno, director of the Research Institute for Diseases of Old Age at Juntendo University, Tokyo. "When the neurons die, their content is expelled into the extraneural space in the medulla oblongata." Other nerve terminals pick up this intracellular debris and die as well, expelling their own contents as damage progresses. "Eventually, this reaches the substantia nigra and the higher cerebellar neurons. This, I believe, is the model for the spread of Parkinson’s."

Constipation can be one of the first symptoms, occurring when Lewy body lesions first appear on the vagal nerve’s dorsal motor nucleus. This is generally 15-20 years before the onset of motor symptoms, Dr. Mizuno said.

The Honolulu Heart Program study clearly showed the association between Parkinson’s disease and constipation. The study followed almost 7,000 men. Over an average of 12 years, 96 developed Parkinson’s disease. In a multivariate analysis, men who had fewer than one bowel movement per day were four times more likely to develop the disease than were men with two or more bowel movements per day (Neurology 2001;57:456-62).

"I think most of these patients already had Parkinson’s before the onset of motor symptoms," he said.

As cell death proceeds along the nerve, it can affect cardiac innervation. Cardiac scintigraphy with the imaging agent iodine-123 metaiodobenzylguanidine (MIBG) highlights norepinephrine transport cells in the normal heart. "In patients with Parkinson’s and dementia with Lewy bodies, you don’t see this, because of the loss of postganglionic parasympathetic nerve fibers," Dr. Mizuno said. "In Alzheimer’s, as well as in progressive supranuclear palsy and multisystem atrophy, you do have nice visualization of these fibers, and this is a very useful test for differentiating Lewy body disorders from these other diseases."

His own studies suggest that MIBG cardiac uptake may parallel the progression of Parkinson’s disease. About half of patients with stage 1 disease show reduced uptake, but "there is much more markedly diminished cardiac MIBG uptake in those with stage 2 disease or higher," Dr. Mizuno said.

Disordered sleep can occur when cell damage advances to the pons – about 10 years before motor symptoms are apparent. "Half of the patients with idiopathic REM sleep disorder will go on to develop Parkinson’s disease," he said.

As nerve damage progresses further, the olfactory bulb may be affected. Hyposmia affects most (80%) Parkinson’s patients, but about 40% report a decline in olfactory function before the onset of motor symptoms. "The interval between hyposmia and motor symptom onset is about 5 years," Dr. Mizuno said.

The characteristic motor symptoms appear only when most of the dopaminergic neurons in the substantia nigra have died. If the damage progresses further, the cortex may be affected, leading to dementia.

"If you compare clinical and lab findings in Parkinson’s disease dementia and dementia with Lewy bodies, you will notice a lot of similarities: constipation, loss of smell, executive dysfunction, fluctuating cognition, and visuospatial dysfunction," Dr. Mizuno said. "The only difference between the two is the presentation of initial symptoms. If motor symptoms appear first, we call it Parkinson’s disease, while if dementia is the initial symptom, we call it dementia with Lewy bodies."

Dr. Mizuno declared no potential financial conflicts of interest.