Jeff Evans

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes mellitus (30% vs. 25%, respectively), history of myocardial infarction (37% vs. 32%), and high cholesterol (51% vs. 45%).

In a conditional logistic regression analysis, the investigators found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post-cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” Dr. Gottesman and her associates suggested. Studies are needed to determine whether having normal hemoglobin levels would decrease the risk of stroke.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes mellitus (30% vs. 25%, respectively), history of myocardial infarction (37% vs. 32%), and high cholesterol (51% vs. 45%).

In a conditional logistic regression analysis, the investigators found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post-cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” Dr. Gottesman and her associates suggested. Studies are needed to determine whether having normal hemoglobin levels would decrease the risk of stroke.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes mellitus (30% vs. 25%, respectively), history of myocardial infarction (37% vs. 32%), and high cholesterol (51% vs. 45%).

In a conditional logistic regression analysis, the investigators found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post-cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” Dr. Gottesman and her associates suggested. Studies are needed to determine whether having normal hemoglobin levels would decrease the risk of stroke.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

BALTIMORE — A test battery of three oculomotor signs for patients with acute vestibular syndrome can detect stroke with greater sensitivity than does MRI with diffusion-weighted imaging in the first 24-48 hours after symptom onset, according to a prospective, cross-sectional study.

If the results are confirmed in a larger, multicenter study, they will help determine which patients with acute vestibular syndrome (AVS) should undergo MRI scanning, Dr. David E. Newman-Toker said at the annual meeting of the American Neurological Association.

MRI scanning of all patients with AVS is “probably an unrealistic strategy” for diagnosis, said Dr. Newman-Toker of the departments of neurology and ophthalmology at Johns Hopkins University, Baltimore.

Of 2.6 million visits to the emergency department for dizziness each year, about 5% (or 100,000-150,000 people) have a cerebrovascular event, mostly in the lateral brainstem or the inferior cerebellum (Mayo Clin. Proc. 2008;83:765-75). Of that 5%, evidence suggests that approximately 35% may be misdiagnosed, which is a much higher rate than with other types of stroke (Stroke 2006;37:2484-7). Another study reported that around 40% of these misdiagnoses culminate in death or disability.

Strokes in the lateral brainstem or the inferior cerebellum frequently mimic benign vestibular disorders, such as vestibular neuritis or labyrinthitis, which are collectively known as acute peripheral vestibulopathies.

To determine if a battery of bedside oculomotor signs could detect patients with stroke with greater accuracy than did early MRI with diffusion-weighted imaging (DWI), the investigators prospectively enrolled 101 patients during 1999-2008 who presented with AVS to an urban academic acute stroke referral center. AVS is a rapid onset of a new persistent dizziness or vertigo that is sustained for 12-24 hours with some degree of gait unsteadiness, in association with head-motion intolerance and nystagmus, nausea, and vomiting.

The patients were admitted either through the academic medical center's emergency department or by transfer from other hospitals. They only included patients who had at least one risk factor for stroke.

Each patient underwent MRI scanning with DWI, which was repeated if the initial MRI was negative but oculomotor and other neurologic signs indicated stroke. “This distinguishes this study from every other study to date on this subject, where it was assumed that the initial MRI scan in those studies was accurate, which was not necessarily a safe assumption,” Dr. Newman-Toker said.

One investigator performed the test battery for oculomotor signs of stroke—given the mnemonic HINTS: head impulse test, nystagmus, and test of skew.

These are assessed by performing a horizontal head impulse test (a test of vestibulo-ocular reflex function), a test for direction-changing nystagmus, and an alternating cover test to test for skew deviation. The results of each test have been individually associated with stroke in AVS (Stroke 2009;40:3504-10).

Men accounted for 65% of the enrolled patients, who had a mean age of 62 years. Most patients (70%) had two or more stroke risk factors, “so this was a very high risk for stroke population,” he noted.

Three-fourths of the patients were examined within 24 hours of symptom onset and about 70% underwent an MRI scan within 6 hours of their bedside exam. A single examiner, who was blinded only to the MRI findings, performed all of the neurologic exams.

Based on the reference standard of MRI with DWI for diagnosis, 25 patients had peripheral vestibulopathy (vestibular neuritis or labyrinthitis) and 76 had central brain pathology (69 ischemic strokes, 4 hemorrhages, 2 demyelinating diseases, and 1 acute intoxication with an anticonvulsant).

Testing for HINTS to INFARCT (Impulse Normal, Fast-Phase Alternating, or Refixation on Cover Test) detected stroke with 100% sensitivity and 96% specificity. In contrast, an initial MRI with DWI detected stroke with 88% sensitivity and 100% specificity. The use of any obvious neurologic signs for detecting stroke (such as limb ataxia, severe truncal ataxia, hemiparesis, or gaze palsy) provided a sensitivity of 64% with 100% specificity. General neurologic signs had only 19% sensitivity and 100% specificity. A normal horizontal head impulse test was the best single predictor of stroke with 90% sensitivity and 100% specificity, although it misses lateral pontine strokes because the reflex pathway tracks from the inner ear straight to the pons.

Peripheral vestibulopathies occurred in patients with an abnormal head impulse test, direction-fixed nystagmus, and no skew deviation.

The study was funded by grants from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Newman-Toker reported having no relevant disclosures.

BALTIMORE — A test battery of three oculomotor signs for patients with acute vestibular syndrome can detect stroke with greater sensitivity than does MRI with diffusion-weighted imaging in the first 24-48 hours after symptom onset, according to a prospective, cross-sectional study.

If the results are confirmed in a larger, multicenter study, they will help determine which patients with acute vestibular syndrome (AVS) should undergo MRI scanning, Dr. David E. Newman-Toker said at the annual meeting of the American Neurological Association.

MRI scanning of all patients with AVS is “probably an unrealistic strategy” for diagnosis, said Dr. Newman-Toker of the departments of neurology and ophthalmology at Johns Hopkins University, Baltimore.

Of 2.6 million visits to the emergency department for dizziness each year, about 5% (or 100,000-150,000 people) have a cerebrovascular event, mostly in the lateral brainstem or the inferior cerebellum (Mayo Clin. Proc. 2008;83:765-75). Of that 5%, evidence suggests that approximately 35% may be misdiagnosed, which is a much higher rate than with other types of stroke (Stroke 2006;37:2484-7). Another study reported that around 40% of these misdiagnoses culminate in death or disability.

Strokes in the lateral brainstem or the inferior cerebellum frequently mimic benign vestibular disorders, such as vestibular neuritis or labyrinthitis, which are collectively known as acute peripheral vestibulopathies.

To determine if a battery of bedside oculomotor signs could detect patients with stroke with greater accuracy than did early MRI with diffusion-weighted imaging (DWI), the investigators prospectively enrolled 101 patients during 1999-2008 who presented with AVS to an urban academic acute stroke referral center. AVS is a rapid onset of a new persistent dizziness or vertigo that is sustained for 12-24 hours with some degree of gait unsteadiness, in association with head-motion intolerance and nystagmus, nausea, and vomiting.

The patients were admitted either through the academic medical center's emergency department or by transfer from other hospitals. They only included patients who had at least one risk factor for stroke.

Each patient underwent MRI scanning with DWI, which was repeated if the initial MRI was negative but oculomotor and other neurologic signs indicated stroke. “This distinguishes this study from every other study to date on this subject, where it was assumed that the initial MRI scan in those studies was accurate, which was not necessarily a safe assumption,” Dr. Newman-Toker said.

One investigator performed the test battery for oculomotor signs of stroke—given the mnemonic HINTS: head impulse test, nystagmus, and test of skew.

These are assessed by performing a horizontal head impulse test (a test of vestibulo-ocular reflex function), a test for direction-changing nystagmus, and an alternating cover test to test for skew deviation. The results of each test have been individually associated with stroke in AVS (Stroke 2009;40:3504-10).

Men accounted for 65% of the enrolled patients, who had a mean age of 62 years. Most patients (70%) had two or more stroke risk factors, “so this was a very high risk for stroke population,” he noted.

Three-fourths of the patients were examined within 24 hours of symptom onset and about 70% underwent an MRI scan within 6 hours of their bedside exam. A single examiner, who was blinded only to the MRI findings, performed all of the neurologic exams.

Based on the reference standard of MRI with DWI for diagnosis, 25 patients had peripheral vestibulopathy (vestibular neuritis or labyrinthitis) and 76 had central brain pathology (69 ischemic strokes, 4 hemorrhages, 2 demyelinating diseases, and 1 acute intoxication with an anticonvulsant).

Testing for HINTS to INFARCT (Impulse Normal, Fast-Phase Alternating, or Refixation on Cover Test) detected stroke with 100% sensitivity and 96% specificity. In contrast, an initial MRI with DWI detected stroke with 88% sensitivity and 100% specificity. The use of any obvious neurologic signs for detecting stroke (such as limb ataxia, severe truncal ataxia, hemiparesis, or gaze palsy) provided a sensitivity of 64% with 100% specificity. General neurologic signs had only 19% sensitivity and 100% specificity. A normal horizontal head impulse test was the best single predictor of stroke with 90% sensitivity and 100% specificity, although it misses lateral pontine strokes because the reflex pathway tracks from the inner ear straight to the pons.

Peripheral vestibulopathies occurred in patients with an abnormal head impulse test, direction-fixed nystagmus, and no skew deviation.

The study was funded by grants from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Newman-Toker reported having no relevant disclosures.

BALTIMORE — A test battery of three oculomotor signs for patients with acute vestibular syndrome can detect stroke with greater sensitivity than does MRI with diffusion-weighted imaging in the first 24-48 hours after symptom onset, according to a prospective, cross-sectional study.

If the results are confirmed in a larger, multicenter study, they will help determine which patients with acute vestibular syndrome (AVS) should undergo MRI scanning, Dr. David E. Newman-Toker said at the annual meeting of the American Neurological Association.

MRI scanning of all patients with AVS is “probably an unrealistic strategy” for diagnosis, said Dr. Newman-Toker of the departments of neurology and ophthalmology at Johns Hopkins University, Baltimore.

Of 2.6 million visits to the emergency department for dizziness each year, about 5% (or 100,000-150,000 people) have a cerebrovascular event, mostly in the lateral brainstem or the inferior cerebellum (Mayo Clin. Proc. 2008;83:765-75). Of that 5%, evidence suggests that approximately 35% may be misdiagnosed, which is a much higher rate than with other types of stroke (Stroke 2006;37:2484-7). Another study reported that around 40% of these misdiagnoses culminate in death or disability.

Strokes in the lateral brainstem or the inferior cerebellum frequently mimic benign vestibular disorders, such as vestibular neuritis or labyrinthitis, which are collectively known as acute peripheral vestibulopathies.

To determine if a battery of bedside oculomotor signs could detect patients with stroke with greater accuracy than did early MRI with diffusion-weighted imaging (DWI), the investigators prospectively enrolled 101 patients during 1999-2008 who presented with AVS to an urban academic acute stroke referral center. AVS is a rapid onset of a new persistent dizziness or vertigo that is sustained for 12-24 hours with some degree of gait unsteadiness, in association with head-motion intolerance and nystagmus, nausea, and vomiting.

The patients were admitted either through the academic medical center's emergency department or by transfer from other hospitals. They only included patients who had at least one risk factor for stroke.

Each patient underwent MRI scanning with DWI, which was repeated if the initial MRI was negative but oculomotor and other neurologic signs indicated stroke. “This distinguishes this study from every other study to date on this subject, where it was assumed that the initial MRI scan in those studies was accurate, which was not necessarily a safe assumption,” Dr. Newman-Toker said.

One investigator performed the test battery for oculomotor signs of stroke—given the mnemonic HINTS: head impulse test, nystagmus, and test of skew.

These are assessed by performing a horizontal head impulse test (a test of vestibulo-ocular reflex function), a test for direction-changing nystagmus, and an alternating cover test to test for skew deviation. The results of each test have been individually associated with stroke in AVS (Stroke 2009;40:3504-10).

Men accounted for 65% of the enrolled patients, who had a mean age of 62 years. Most patients (70%) had two or more stroke risk factors, “so this was a very high risk for stroke population,” he noted.

Three-fourths of the patients were examined within 24 hours of symptom onset and about 70% underwent an MRI scan within 6 hours of their bedside exam. A single examiner, who was blinded only to the MRI findings, performed all of the neurologic exams.

Based on the reference standard of MRI with DWI for diagnosis, 25 patients had peripheral vestibulopathy (vestibular neuritis or labyrinthitis) and 76 had central brain pathology (69 ischemic strokes, 4 hemorrhages, 2 demyelinating diseases, and 1 acute intoxication with an anticonvulsant).

Testing for HINTS to INFARCT (Impulse Normal, Fast-Phase Alternating, or Refixation on Cover Test) detected stroke with 100% sensitivity and 96% specificity. In contrast, an initial MRI with DWI detected stroke with 88% sensitivity and 100% specificity. The use of any obvious neurologic signs for detecting stroke (such as limb ataxia, severe truncal ataxia, hemiparesis, or gaze palsy) provided a sensitivity of 64% with 100% specificity. General neurologic signs had only 19% sensitivity and 100% specificity. A normal horizontal head impulse test was the best single predictor of stroke with 90% sensitivity and 100% specificity, although it misses lateral pontine strokes because the reflex pathway tracks from the inner ear straight to the pons.

Peripheral vestibulopathies occurred in patients with an abnormal head impulse test, direction-fixed nystagmus, and no skew deviation.

The study was funded by grants from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Newman-Toker reported having no relevant disclosures.

BALTIMORE – Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients who have an atypical presentation of Alzheimer's disease (AD) but nonetheless have the amyloid-beta plaques and neurofibrillary tangles of tau protein that pathologically diagnose the disease have much less hippocampal atrophy than do patients who present with the typical clinical characteristics used to diagnose AD–loss of episodic memory, executive dysfunction, visuospatial and perceptual deficits, and language dysfunction, Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Patients who do not have those symptoms are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), such as FTLD with the deposition of TAR-DNA binding protein-43 (TDP-43), corticobasal degeneration pathology, Pick's disease pathology, or progressive supranuclear palsy pathology.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging rather than by imaging amyloid-beta or tau proteins.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI). They also had at least one volumetric MRI scan.

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

The typical AD patients showed the expected areas of atrophy in the temporoparietal cortex and hippocampi. However, atypical AD patients had temporoparietal atrophy but no hippocampal atrophy. FTLD patients had anterior-temporal, some posterior-frontal, and hippocampal atrophy.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one specific clinical dementia subtype.

“Temporoparietal atrophy may be a signature of Alzheimer's disease independent of syndromic presentation. … Hippocampal atrophy does not appear to be at least an early prominent feature of atypical Alzheimer's disease. Later on, 5–6 years down the road, as the process progresses and there's degeneration, well, you might find hippocampal atrophy then,” Dr. Josephs said.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical Alzheimer's disease, compared with typical AD and frontotemporal lobar degeneration.

Source Images courtesy Jennifer Whitwell, Ph.D.

BALTIMORE – Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients who have an atypical presentation of Alzheimer's disease (AD) but nonetheless have the amyloid-beta plaques and neurofibrillary tangles of tau protein that pathologically diagnose the disease have much less hippocampal atrophy than do patients who present with the typical clinical characteristics used to diagnose AD–loss of episodic memory, executive dysfunction, visuospatial and perceptual deficits, and language dysfunction, Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Patients who do not have those symptoms are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), such as FTLD with the deposition of TAR-DNA binding protein-43 (TDP-43), corticobasal degeneration pathology, Pick's disease pathology, or progressive supranuclear palsy pathology.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging rather than by imaging amyloid-beta or tau proteins.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI). They also had at least one volumetric MRI scan.

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

The typical AD patients showed the expected areas of atrophy in the temporoparietal cortex and hippocampi. However, atypical AD patients had temporoparietal atrophy but no hippocampal atrophy. FTLD patients had anterior-temporal, some posterior-frontal, and hippocampal atrophy.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one specific clinical dementia subtype.

“Temporoparietal atrophy may be a signature of Alzheimer's disease independent of syndromic presentation. … Hippocampal atrophy does not appear to be at least an early prominent feature of atypical Alzheimer's disease. Later on, 5–6 years down the road, as the process progresses and there's degeneration, well, you might find hippocampal atrophy then,” Dr. Josephs said.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical Alzheimer's disease, compared with typical AD and frontotemporal lobar degeneration.

Source Images courtesy Jennifer Whitwell, Ph.D.

BALTIMORE – Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients who have an atypical presentation of Alzheimer's disease (AD) but nonetheless have the amyloid-beta plaques and neurofibrillary tangles of tau protein that pathologically diagnose the disease have much less hippocampal atrophy than do patients who present with the typical clinical characteristics used to diagnose AD–loss of episodic memory, executive dysfunction, visuospatial and perceptual deficits, and language dysfunction, Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Patients who do not have those symptoms are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), such as FTLD with the deposition of TAR-DNA binding protein-43 (TDP-43), corticobasal degeneration pathology, Pick's disease pathology, or progressive supranuclear palsy pathology.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging rather than by imaging amyloid-beta or tau proteins.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI). They also had at least one volumetric MRI scan.

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

The typical AD patients showed the expected areas of atrophy in the temporoparietal cortex and hippocampi. However, atypical AD patients had temporoparietal atrophy but no hippocampal atrophy. FTLD patients had anterior-temporal, some posterior-frontal, and hippocampal atrophy.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one specific clinical dementia subtype.

“Temporoparietal atrophy may be a signature of Alzheimer's disease independent of syndromic presentation. … Hippocampal atrophy does not appear to be at least an early prominent feature of atypical Alzheimer's disease. Later on, 5–6 years down the road, as the process progresses and there's degeneration, well, you might find hippocampal atrophy then,” Dr. Josephs said.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical Alzheimer's disease, compared with typical AD and frontotemporal lobar degeneration.

Source Images courtesy Jennifer Whitwell, Ph.D.

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best combination of accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies necessary to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

“These technologies … have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus (BE)—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with BE who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology Guidelines for BE Surveillance.

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients referred for BE screening or surveillance. They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of BE. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) lesions found in the patients also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

Dr. Sharma receives grant and research support from Olympus America, manufacturer of the NBI device used in the study, and from Mauna Kea Technologies. The American Society for Gastrointestinal Endoscopy funded the study.

NBI shows irregular dysplastic Barrett's, confirmed by biopsy.

White light endoscopy shows nondysplastic Barrett's esophagus.

Source Images courtesy Dr. Prateek Sharma

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best combination of accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies necessary to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

“These technologies … have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus (BE)—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with BE who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology Guidelines for BE Surveillance.

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients referred for BE screening or surveillance. They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of BE. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) lesions found in the patients also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

Dr. Sharma receives grant and research support from Olympus America, manufacturer of the NBI device used in the study, and from Mauna Kea Technologies. The American Society for Gastrointestinal Endoscopy funded the study.

NBI shows irregular dysplastic Barrett's, confirmed by biopsy.

White light endoscopy shows nondysplastic Barrett's esophagus.

Source Images courtesy Dr. Prateek Sharma

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best combination of accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies necessary to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

“These technologies … have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus (BE)—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with BE who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology Guidelines for BE Surveillance.

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients referred for BE screening or surveillance. They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of BE. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) lesions found in the patients also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

Dr. Sharma receives grant and research support from Olympus America, manufacturer of the NBI device used in the study, and from Mauna Kea Technologies. The American Society for Gastrointestinal Endoscopy funded the study.

NBI shows irregular dysplastic Barrett's, confirmed by biopsy.

White light endoscopy shows nondysplastic Barrett's esophagus.

Source Images courtesy Dr. Prateek Sharma

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam content outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts. These 10 mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam content outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts. These 10 mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam content outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts. These 10 mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances this summer.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications. And the reason for that is we believe that science has taken us up to a point where we are concerned,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press conference at the society's annual meeting.

Researchers at the meeting also presented new animal studies on the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestational development, as well as the possible continual exposure of the majority of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing the evidence of the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, who noted that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

The scientific statement is published in the June issue of Endocrine Reviews (2009;30:293–342).

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA, which is a synthetic monomer used in the production of polycarbonate plastics and epoxy resins, as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE.

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the development of the uterus. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri–Columbia, also reported a study at the press conference. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA. But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8–9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done … [and] we can't afford to wait until we have perfect data in humans. When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling.”

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Medicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

Bisphenol A, found in products such as plastic water bottles, was among the endocrine disruptors discussed at the meeting.

Source Courtesy University of Cincinnati

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances this summer.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications. And the reason for that is we believe that science has taken us up to a point where we are concerned,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press conference at the society's annual meeting.

Researchers at the meeting also presented new animal studies on the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestational development, as well as the possible continual exposure of the majority of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing the evidence of the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, who noted that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

The scientific statement is published in the June issue of Endocrine Reviews (2009;30:293–342).

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA, which is a synthetic monomer used in the production of polycarbonate plastics and epoxy resins, as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE.

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the development of the uterus. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri–Columbia, also reported a study at the press conference. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA. But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8–9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done … [and] we can't afford to wait until we have perfect data in humans. When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling.”

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Medicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

Bisphenol A, found in products such as plastic water bottles, was among the endocrine disruptors discussed at the meeting.

Source Courtesy University of Cincinnati

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances this summer.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications. And the reason for that is we believe that science has taken us up to a point where we are concerned,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press conference at the society's annual meeting.

Researchers at the meeting also presented new animal studies on the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestational development, as well as the possible continual exposure of the majority of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing the evidence of the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, who noted that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

The scientific statement is published in the June issue of Endocrine Reviews (2009;30:293–342).

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA, which is a synthetic monomer used in the production of polycarbonate plastics and epoxy resins, as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE.

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the development of the uterus. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri–Columbia, also reported a study at the press conference. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA. But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8–9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done … [and] we can't afford to wait until we have perfect data in humans. When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling.”

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Medicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

Bisphenol A, found in products such as plastic water bottles, was among the endocrine disruptors discussed at the meeting.

Source Courtesy University of Cincinnati

WASHINGTON — Female infants born to women with polycystic ovary syndrome do not appear to have high levels of androgens or to be small for gestational age, based on the results of a prospective, case-control study.

In fact, offspring born to mothers with polycystic ovary syndrome (PCOS) were more likely than controls to be large for gestational age.

Findings from clinical and animal-based studies suggest that PCOS may originate during fetal development. Prenatal exposure to androgens has been shown to induce a PCOS phenotype in sheep, monkeys, and rats. In humans, retrospective studies have demonstrated that girls with PCOS features and premature menarche had been significantly small for their gestational age, according to Helen Anderson of the division of endocrinology, metabolism, and molecular medicine at Northwestern University, Chicago.

To determine if the intrauterine environment of women with PCOS alters fetal growth and androgen levels, Ms. Anderson and her associates compared singleton pregnancies in 39 women with PCOS and 31 healthy control women. The participants were non-Hispanic white women who met National Institute of Child Health and Human Development criteria for PCOS. Women with PCOS had less then six menses per year, whereas healthy control women had a history of regular menses. None of the participants had a history of gestational diabetes, preexisting medical conditions, or complications during pregnancy.

Compared with healthy controls, a larger percentage of women with PCOS were nulliparous (64% vs. 39%) or had undergone ovulation induction or in vitro fertilization (77% vs. 6%). Women with PCOS were slightly, but significantly, younger than the healthy control women (30 years vs. 32 years). Although PCOS women had a slightly higher mean body mass index than did control women, they had comparable maternal weight gains.

The birth cohort consisted of more females (43) than males (27) because the investigators were primarily interested in female offspring, and they excluded women known to be carrying a male fetus.

Overall, the gestational age and birth weight of infants did not differ between women with and without PCOS. However, when Ms. Anderson and her colleagues stratified the analysis according to size at gestational age, a significantly greater proportion of the infants born to women with PCOS were large for gestational age (greater than 90th percentile), compared with healthy controls (23% vs. 3%).

“This may be secondary to the increased nutritional flow across the placenta,” as elevated levels of insulin and glucose have been demonstrated in pregnant women with PCOS, Ms. Anderson said at the annual meeting of the Endocrine Society.

Analyses of the steroid hormones in whole (mixed arterial and venous) cord blood showed that the female offspring of PCOS women had significantly lower levels of androstenedione and estradiol than did the female offspring of controls.

However, female offspring had no differences in levels of testosterone, dihydrotestosterone, and dehydroepiandrosterone, although Ms. Anderson said that many of the testosterone and dihydrotestosterone values were at the low end of detectability for the assays.

Female offspring from either group of women showed no differences in levels of 17-hydroxyprogesterone or in the ratio of testosterone to estradiol levels.

The National Institutes of Health funded the study. Ms. Anderson reported having no conflicts of interest to disclose.

Female offspring of mothers with PCOS were more likely than controls to be large for gestational age.

Source MS. ANDERSON

WASHINGTON — Female infants born to women with polycystic ovary syndrome do not appear to have high levels of androgens or to be small for gestational age, based on the results of a prospective, case-control study.

In fact, offspring born to mothers with polycystic ovary syndrome (PCOS) were more likely than controls to be large for gestational age.

Findings from clinical and animal-based studies suggest that PCOS may originate during fetal development. Prenatal exposure to androgens has been shown to induce a PCOS phenotype in sheep, monkeys, and rats. In humans, retrospective studies have demonstrated that girls with PCOS features and premature menarche had been significantly small for their gestational age, according to Helen Anderson of the division of endocrinology, metabolism, and molecular medicine at Northwestern University, Chicago.

To determine if the intrauterine environment of women with PCOS alters fetal growth and androgen levels, Ms. Anderson and her associates compared singleton pregnancies in 39 women with PCOS and 31 healthy control women. The participants were non-Hispanic white women who met National Institute of Child Health and Human Development criteria for PCOS. Women with PCOS had less then six menses per year, whereas healthy control women had a history of regular menses. None of the participants had a history of gestational diabetes, preexisting medical conditions, or complications during pregnancy.

Compared with healthy controls, a larger percentage of women with PCOS were nulliparous (64% vs. 39%) or had undergone ovulation induction or in vitro fertilization (77% vs. 6%). Women with PCOS were slightly, but significantly, younger than the healthy control women (30 years vs. 32 years). Although PCOS women had a slightly higher mean body mass index than did control women, they had comparable maternal weight gains.

The birth cohort consisted of more females (43) than males (27) because the investigators were primarily interested in female offspring, and they excluded women known to be carrying a male fetus.

Overall, the gestational age and birth weight of infants did not differ between women with and without PCOS. However, when Ms. Anderson and her colleagues stratified the analysis according to size at gestational age, a significantly greater proportion of the infants born to women with PCOS were large for gestational age (greater than 90th percentile), compared with healthy controls (23% vs. 3%).

“This may be secondary to the increased nutritional flow across the placenta,” as elevated levels of insulin and glucose have been demonstrated in pregnant women with PCOS, Ms. Anderson said at the annual meeting of the Endocrine Society.

Analyses of the steroid hormones in whole (mixed arterial and venous) cord blood showed that the female offspring of PCOS women had significantly lower levels of androstenedione and estradiol than did the female offspring of controls.

However, female offspring had no differences in levels of testosterone, dihydrotestosterone, and dehydroepiandrosterone, although Ms. Anderson said that many of the testosterone and dihydrotestosterone values were at the low end of detectability for the assays.

Female offspring from either group of women showed no differences in levels of 17-hydroxyprogesterone or in the ratio of testosterone to estradiol levels.

The National Institutes of Health funded the study. Ms. Anderson reported having no conflicts of interest to disclose.

Female offspring of mothers with PCOS were more likely than controls to be large for gestational age.

Source MS. ANDERSON

WASHINGTON — Female infants born to women with polycystic ovary syndrome do not appear to have high levels of androgens or to be small for gestational age, based on the results of a prospective, case-control study.

In fact, offspring born to mothers with polycystic ovary syndrome (PCOS) were more likely than controls to be large for gestational age.

Findings from clinical and animal-based studies suggest that PCOS may originate during fetal development. Prenatal exposure to androgens has been shown to induce a PCOS phenotype in sheep, monkeys, and rats. In humans, retrospective studies have demonstrated that girls with PCOS features and premature menarche had been significantly small for their gestational age, according to Helen Anderson of the division of endocrinology, metabolism, and molecular medicine at Northwestern University, Chicago.

To determine if the intrauterine environment of women with PCOS alters fetal growth and androgen levels, Ms. Anderson and her associates compared singleton pregnancies in 39 women with PCOS and 31 healthy control women. The participants were non-Hispanic white women who met National Institute of Child Health and Human Development criteria for PCOS. Women with PCOS had less then six menses per year, whereas healthy control women had a history of regular menses. None of the participants had a history of gestational diabetes, preexisting medical conditions, or complications during pregnancy.

Compared with healthy controls, a larger percentage of women with PCOS were nulliparous (64% vs. 39%) or had undergone ovulation induction or in vitro fertilization (77% vs. 6%). Women with PCOS were slightly, but significantly, younger than the healthy control women (30 years vs. 32 years). Although PCOS women had a slightly higher mean body mass index than did control women, they had comparable maternal weight gains.

The birth cohort consisted of more females (43) than males (27) because the investigators were primarily interested in female offspring, and they excluded women known to be carrying a male fetus.

Overall, the gestational age and birth weight of infants did not differ between women with and without PCOS. However, when Ms. Anderson and her colleagues stratified the analysis according to size at gestational age, a significantly greater proportion of the infants born to women with PCOS were large for gestational age (greater than 90th percentile), compared with healthy controls (23% vs. 3%).

“This may be secondary to the increased nutritional flow across the placenta,” as elevated levels of insulin and glucose have been demonstrated in pregnant women with PCOS, Ms. Anderson said at the annual meeting of the Endocrine Society.

Analyses of the steroid hormones in whole (mixed arterial and venous) cord blood showed that the female offspring of PCOS women had significantly lower levels of androstenedione and estradiol than did the female offspring of controls.

However, female offspring had no differences in levels of testosterone, dihydrotestosterone, and dehydroepiandrosterone, although Ms. Anderson said that many of the testosterone and dihydrotestosterone values were at the low end of detectability for the assays.

Female offspring from either group of women showed no differences in levels of 17-hydroxyprogesterone or in the ratio of testosterone to estradiol levels.

The National Institutes of Health funded the study. Ms. Anderson reported having no conflicts of interest to disclose.

Female offspring of mothers with PCOS were more likely than controls to be large for gestational age.

Source MS. ANDERSON

BALTIMORE — Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients with Alzheimer's disease (AD) who do not show its typical clinical characteristics—loss of episodic memory, executive dysfunction, language dysfunction, and visuospatial and perceptual deficits—are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI).

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one clinical dementia subtype.

In discriminating atypical AD from FTLD, volume loss from the hippocampus gave an area under the receiver operating characteristic curve (AUC) of 0.74, compared with 0.81 for the temporoparietal cortex. The ratio of hippocampal to temporoparietal volume loss provided the best result with an AUC of 0.93.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical AD, compared with typical AD and FTLD.

Source Courtesy Jennifer Whitwell, Ph.D.

BALTIMORE — Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients with Alzheimer's disease (AD) who do not show its typical clinical characteristics—loss of episodic memory, executive dysfunction, language dysfunction, and visuospatial and perceptual deficits—are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI).

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one clinical dementia subtype.

In discriminating atypical AD from FTLD, volume loss from the hippocampus gave an area under the receiver operating characteristic curve (AUC) of 0.74, compared with 0.81 for the temporoparietal cortex. The ratio of hippocampal to temporoparietal volume loss provided the best result with an AUC of 0.93.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical AD, compared with typical AD and FTLD.

Source Courtesy Jennifer Whitwell, Ph.D.

BALTIMORE — Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small MRI scanning study.

Patients with Alzheimer's disease (AD) who do not show its typical clinical characteristics—loss of episodic memory, executive dysfunction, language dysfunction, and visuospatial and perceptual deficits—are usually diagnosed with a frontotemporal dementialike syndrome, progressive aphasia syndrome, or a corticobasal syndrome characterized by asymmetric, extrapyramidal, and cortical dysfunction. However, patients with those symptoms most frequently have a type of frontotemporal lobar degeneration (FTLD), Dr. Keith A. Josephs said at the annual meeting of the American Neurological Association.

Differentiating AD from other dementias is important if future treatments for AD differ from FTLD, “which is likely, given the fact that the proteins that are deposited in Alzheimer's disease differ from the ones in FTLD,” said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn.

To predict AD pathology in patients who present with a range of atypical AD clinical syndromes, Dr. Josephs and his colleagues looked at the gross structure of the brain with volumetric MR imaging.

They found 14 patients at the Mayo Clinic in Rochester who had a diagnosis of atypical AD dementia. These patients were evaluated by a behavioral neurologist and determined not to have a typical presentation of AD but were pathologically confirmed to have a high-probability diagnosis of AD according to National Institute on Aging–Reagan Institute Consensus Conference criteria (Braak stage V or VI).

Of the 14 patients with atypical AD, 6 had aphasic dementia, 5 had a corticobasal syndrome, and 3 had a clinical diagnosis of behavioral-variant frontotemporal degeneration. Dr. Josephs and his associates compared the atypical AD patients with 14 patients with pathologically diagnosed FTLD who had the same clinical dementia syndromes.

They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and 20 healthy control patients.

In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women.

In comparisons between the groups, both typical AD and FTLD patients had more hippocampal atrophy than did atypical AD patients. The atypical AD patients showed more putamenal atrophy than did typical AD patients. The atypical AD patients also had more temporoparietal atrophy than did the FTLD patients.

Patterns of atrophy also tended to vary across the dementia syndrome subtypes found among the atypical AD patients when compared with the healthy control patients, but all of the atypical AD patients had temporoparietal atrophy in common.

In individual analyses of each patient, typical AD and FTLD patients had significantly more hippocampal atrophy than did individual atypical AD patients.

However, individuals with either typical or atypical AD had significantly more temporoparietal atrophy than did FTLD patients. The pattern of atrophy was not driven by one clinical dementia subtype.

In discriminating atypical AD from FTLD, volume loss from the hippocampus gave an area under the receiver operating characteristic curve (AUC) of 0.74, compared with 0.81 for the temporoparietal cortex. The ratio of hippocampal to temporoparietal volume loss provided the best result with an AUC of 0.93.

The study was funded by grants from the National Institutes of Health and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Dr. Josephs had no disclosures to report.

The medial temporal lobes are relatively spared in atypical AD, compared with typical AD and FTLD.

Source Courtesy Jennifer Whitwell, Ph.D.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their exam content outline, or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their exam content outline, or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their exam content outline, or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies needed to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four-quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

These technologies “have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus and potentially help us increase the yield of dysplasia and cancer [and] probably even decrease our biopsy burden,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with Barrett's esophagus who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology guidelines for Barrett's Ssurveillance.

Increasing length of affected tissue was associated with less compliance with the full protocol. Not surprisingly, lower adherence to the protocol was associated with a lower rate of detecting dysplasia, after stratifying the patients based on their length of tissue affected by Barrett's (Clin. Gastroenterol. Hepatol. 2009;7:736-42).

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients who were referred for Barrett's screening or surveillance.

They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

This study design was “rigorous” and “one of the most robust for an imaging study,” he said.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of affected tissue. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

NBI required significantly fewer biopsies per procedure than did HD-WLE (3.6 vs. 7.6).

Dr. Sharma reported that he receives grant and research support from Olympus America, which manufactures the NBI device used in the study, and also from Mauna Kea Technologies.

The American Society for Gastrointestinal Endoscopy funded the study.

NBI could “dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Prateek Sharma said.

Source Courtesy Dr. Prateek Sharma

NBI accurately detects the dysplastic tissue seen in Barrett's esophagus.

White light endoscopy relies on random tissue biopsy to detect Barrett's.

Autofluorescent imaging has a high false-positive rate for Barrett's tissue.

Confocal endomicroscopy may be useful as an adjunct to NBI.

Source Images courtesy Dr. Prateek Sharma

Autofluorescence and Confocal Imaging

Autofluorescence imaging is a “broad-based imaging tool” that can monitor changes in the pattern of distribution of autofluorescent proteins in the esophagus when normal mucosal tissue becomes dysplastic or cancerous, Dr. Prateek Sharma explained.

Tissue patches that are found to be dysplastic or cancerous could then be targeted for biopsy. However, research suggests that autofluorescence imaging may have a false-positive rate that is too high to be useful as a stand-alone screening and surveillance procedure for Barrett's esophagus because tissue patches that have been flagged as dysplastic or cancerous may be normal or inflamed tissue.

In another study presented at Digestive Diseases Week by Dr. Sharma's research group, autofluorescence imaging conducted with a prototype multimodality endoscope from Olympus America Inc. had poorer sensitivity for detecting high-grade dysplasia or cancer than did narrow band imaging (NBI) in 25 patients who were undergoing surveillance of Barrett's or endoscopic treatment of high-grade dysplasia or cancer. Autofluorescence imaging detected a total of 23 abnormal areas in 11 patients, whereas NBI located 19 abnormal areas in 12 patients.

“The jury is still out on autofluorescence, and we still need further studies to define its exact role,” he said.

The broad-based technique of NBI or autofluorescence imaging also might be combined with a third, much more focused technique called confocal endomicroscopy, which is a “way of doing in vivo histology,” Dr. Sharma said.

In areas of tissue that already have been highlighted as abnormal with NBI or autofluorescence imaging, this method could take a micrometer-level view of irregularities in glands, increases in cell sizes, and changes in the entire arrangement of cells. However, no study has yet been published that combines confocal endomicroscopy with another technique.

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies needed to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four-quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

These technologies “have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus and potentially help us increase the yield of dysplasia and cancer [and] probably even decrease our biopsy burden,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with Barrett's esophagus who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology guidelines for Barrett's Ssurveillance.

Increasing length of affected tissue was associated with less compliance with the full protocol. Not surprisingly, lower adherence to the protocol was associated with a lower rate of detecting dysplasia, after stratifying the patients based on their length of tissue affected by Barrett's (Clin. Gastroenterol. Hepatol. 2009;7:736-42).

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients who were referred for Barrett's screening or surveillance.

They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

This study design was “rigorous” and “one of the most robust for an imaging study,” he said.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of affected tissue. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

NBI required significantly fewer biopsies per procedure than did HD-WLE (3.6 vs. 7.6).

Dr. Sharma reported that he receives grant and research support from Olympus America, which manufactures the NBI device used in the study, and also from Mauna Kea Technologies.

The American Society for Gastrointestinal Endoscopy funded the study.

NBI could “dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Prateek Sharma said.

Source Courtesy Dr. Prateek Sharma

NBI accurately detects the dysplastic tissue seen in Barrett's esophagus.

White light endoscopy relies on random tissue biopsy to detect Barrett's.

Autofluorescent imaging has a high false-positive rate for Barrett's tissue.

Confocal endomicroscopy may be useful as an adjunct to NBI.

Source Images courtesy Dr. Prateek Sharma

Autofluorescence and Confocal Imaging

Autofluorescence imaging is a “broad-based imaging tool” that can monitor changes in the pattern of distribution of autofluorescent proteins in the esophagus when normal mucosal tissue becomes dysplastic or cancerous, Dr. Prateek Sharma explained.

Tissue patches that are found to be dysplastic or cancerous could then be targeted for biopsy. However, research suggests that autofluorescence imaging may have a false-positive rate that is too high to be useful as a stand-alone screening and surveillance procedure for Barrett's esophagus because tissue patches that have been flagged as dysplastic or cancerous may be normal or inflamed tissue.

In another study presented at Digestive Diseases Week by Dr. Sharma's research group, autofluorescence imaging conducted with a prototype multimodality endoscope from Olympus America Inc. had poorer sensitivity for detecting high-grade dysplasia or cancer than did narrow band imaging (NBI) in 25 patients who were undergoing surveillance of Barrett's or endoscopic treatment of high-grade dysplasia or cancer. Autofluorescence imaging detected a total of 23 abnormal areas in 11 patients, whereas NBI located 19 abnormal areas in 12 patients.

“The jury is still out on autofluorescence, and we still need further studies to define its exact role,” he said.

The broad-based technique of NBI or autofluorescence imaging also might be combined with a third, much more focused technique called confocal endomicroscopy, which is a “way of doing in vivo histology,” Dr. Sharma said.

In areas of tissue that already have been highlighted as abnormal with NBI or autofluorescence imaging, this method could take a micrometer-level view of irregularities in glands, increases in cell sizes, and changes in the entire arrangement of cells. However, no study has yet been published that combines confocal endomicroscopy with another technique.

White light endoscopic methods for Barrett's esophagus screening and surveillance could soon be overtaken by more accurate endoscopic techniques, the most promising of which appears to be narrow band imaging, based on new research.

Narrow band imaging (NBI) may offer the best accuracy in detecting metaplasia, dysplasia, and cancer while reducing the number of biopsies needed to detect changes in esophageal tissue.

White light endoscopy typically relies on random biopsy sampling using the four-quadrant protocol to detect tissue changes, which endoscopists adhere to poorly, said Dr. Prateek Sharma, professor of medicine at the University of Kansas and the Veterans Affair Medical Center, Kansas City.

Other techniques, such as autofluorescence imaging and confocal endomicroscopy, potentially could serve complementary roles to white light endoscopy or NBI during screening and surveillance, said Dr. Sharma, who has evaluated NBI with his colleagues over the past 5 years.

These technologies “have the ability in the future to dramatically change how we do biopsies in patients with Barrett's esophagus and potentially help us increase the yield of dysplasia and cancer [and] probably even decrease our biopsy burden,” Dr. Sharma said in an interview.

The current standard of care for biopsying patients with Barrett's esophagus—the four-quadrant protocol—takes a random tissue biopsy every 90 degrees in every 2-cm length of esophagus that contains Barrett's metaplasia.

Dr. Sharma cited several reasons why the four-quadrant protocol is flawed. The random biopsying may miss dysplastic and cancerous segments in the Barrett's tissue because “if you take a biopsy in the 12 o'clock position, you are hoping that the dysplasia or early cancer is also in that position. It could be in the 1 o'clock or 2 o'clock position and you would just miss it.”

In addition, only about half of patients actually undergo the full biopsy protocol. A recent study of nearly 11,000 patients with Barrett's esophagus who were undergoing surveillance biopsying in the Caris Diagnostics pathology database found that only 51% of patients underwent the full biopsy protocol as recommended by the American College of Gastroenterology guidelines for Barrett's Ssurveillance.

Increasing length of affected tissue was associated with less compliance with the full protocol. Not surprisingly, lower adherence to the protocol was associated with a lower rate of detecting dysplasia, after stratifying the patients based on their length of tissue affected by Barrett's (Clin. Gastroenterol. Hepatol. 2009;7:736-42).

During esophageal endoscopy with NBI, white light is filtered to pass blue light (and some green light) to shine on esophageal tissue. Because hemoglobin in blood selectively absorbs blue light, clinicians can look for irregularities in the patterns of blood vessels or surface mucosa, which have been correlated with histologic findings of dysplasia or cancer in previous studies.

To determine if targeted biopsies with NBI could detect Barrett's metaplasia and dysplasia or cancer better than does high-definition white light endoscopy (HD-WLE) alone, Dr. Sharma and his colleagues at the VA Medical Center and two other centers (Amsterdam Medical Center and the Medical University of South Carolina, Charleston) conducted a study of 123 patients who were referred for Barrett's screening or surveillance.

They were randomized to an exam with HD-WLE, followed later by NBI, or first NBI and then HD-WLE. In each case, a separate investigator performed the second procedure 6-8 weeks after the first procedure without knowing the results of the first.

This study design was “rigorous” and “one of the most robust for an imaging study,” he said.

During HD-WLE, the investigators took biopsies with the four-quadrant technique in every 2-cm length of affected tissue. The patients had an average age of nearly 60 years and were mostly men and white.

At the annual Digestive Diseases Week, Dr. Sharma reported that the rate of detection of intestinal metaplasia in the patients' biopsies—the study's primary end point—was 85% for each modality. The detection of patients with neoplasia (low- and high-grade dysplasia and/or cancer) also was not significantly different between NBI (71%) and HD-WLE (55%).

NBI detected more lesions overall with high-grade dysplasia or cancer than did HD-WLE (19 vs. 13). Lesions with any type of dysplasia (low- and high-grade dysplasia and cancer) also were found with NBI significantly more often than with HD-WLE (81 vs. 67).

NBI required significantly fewer biopsies per procedure than did HD-WLE (3.6 vs. 7.6).

Dr. Sharma reported that he receives grant and research support from Olympus America, which manufactures the NBI device used in the study, and also from Mauna Kea Technologies.

The American Society for Gastrointestinal Endoscopy funded the study.

NBI could “dramatically change how we do biopsies in patients with Barrett's esophagus,” Dr. Prateek Sharma said.

Source Courtesy Dr. Prateek Sharma

NBI accurately detects the dysplastic tissue seen in Barrett's esophagus.

White light endoscopy relies on random tissue biopsy to detect Barrett's.

Autofluorescent imaging has a high false-positive rate for Barrett's tissue.

Confocal endomicroscopy may be useful as an adjunct to NBI.

Source Images courtesy Dr. Prateek Sharma

Autofluorescence and Confocal Imaging

Autofluorescence imaging is a “broad-based imaging tool” that can monitor changes in the pattern of distribution of autofluorescent proteins in the esophagus when normal mucosal tissue becomes dysplastic or cancerous, Dr. Prateek Sharma explained.

Tissue patches that are found to be dysplastic or cancerous could then be targeted for biopsy. However, research suggests that autofluorescence imaging may have a false-positive rate that is too high to be useful as a stand-alone screening and surveillance procedure for Barrett's esophagus because tissue patches that have been flagged as dysplastic or cancerous may be normal or inflamed tissue.

In another study presented at Digestive Diseases Week by Dr. Sharma's research group, autofluorescence imaging conducted with a prototype multimodality endoscope from Olympus America Inc. had poorer sensitivity for detecting high-grade dysplasia or cancer than did narrow band imaging (NBI) in 25 patients who were undergoing surveillance of Barrett's or endoscopic treatment of high-grade dysplasia or cancer. Autofluorescence imaging detected a total of 23 abnormal areas in 11 patients, whereas NBI located 19 abnormal areas in 12 patients.

“The jury is still out on autofluorescence, and we still need further studies to define its exact role,” he said.

The broad-based technique of NBI or autofluorescence imaging also might be combined with a third, much more focused technique called confocal endomicroscopy, which is a “way of doing in vivo histology,” Dr. Sharma said.

In areas of tissue that already have been highlighted as abnormal with NBI or autofluorescence imaging, this method could take a micrometer-level view of irregularities in glands, increases in cell sizes, and changes in the entire arrangement of cells. However, no study has yet been published that combines confocal endomicroscopy with another technique.