AAIC Press Release
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AAIC 2013 press room, July 13-18: 617.954.3414
"Developing Topics" at AAIC 2013 Show Cutting Edge Brain Imaging
Techniques, Reveal Problems with Screening and Misdiagnosis
- No evidence found to support general population dementia screening -
- Misdiagnosis of Alzheimer's leads to excess costs -
- Encouraging first reports for tau imaging in Alzheimer's -
BOSTON, July 17, 2013 – Results from four research studies reported at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston range from a review of population-level studies to a single case history, demonstrating the scope of research being pursued by Alzheimer's researchers around the world.
The four studies were presented as "developing topics" at AAIC 2013, which often include last-minute calculations and data analyses. They include:
- A systematic review showed no evidence that screening for dementia in the general population had any effect on patient outcomes. The researchers caution policymakers not to adopt population-based dementia screening without a clear sense of risks and benefits.
- A random sample of Medicare recipients with vascular dementia and Parkinson's disease — who had all been previously misdiagnosed with Alzheimer's — showed that the misdiagnosis led to significant excess costs compared with people who had not been misdiagnosed. Costs decreased quickly after proper diagnosis.
- A PET scan imaging agent known as [11C]PBB3, which shows the tau protein that forms the Alzheimer's "tangles" — one of the two hallmark brain lesions of the disease — showed promising results in a preliminary study of Alzheimer's patients and healthy controls.
- The potential effectiveness of another tau imaging agent, [F-18]-T808, was indicated in the first autopsy examination of a single subject. Brain tissue samples showed evidence of tau in the same areas and amounts as suggested by the imaging drug in the person's PET scan.
"These studies vividly demonstrate the necessity of taking a variety of approaches to effectively diagnosing, treating and preventing Alzheimer's disease," said Maria Carrillo, Ph.D., Alzheimer's Association vice president of medical and scientific affairs. "The Alzheimer's Association takes a broad-based, big-picture approach to funding research and building innovative collaborations to move the field forward. One example is our partnership with the Society of Nuclear Medicine and Molecular Imaging to develop and publish appropriate use criteria for PET brain amyloid imaging to assist Alzheimer's diagnosis."
"By 2050, the cost of caring people with Alzheimer's and other dementias is estimated to be more than $1 trillion annually in the United States alone. It is essential that we continue to gather scientific evidence at all levels, from the individual case study up to large-scale population-based research. The U.S. National Alzheimer's Plan was passed in 2012 and now must be fully implemented, and the commitment by the federal government to spend an additional $100 million on Alzheimer's and dementia research this year must be funded," Carrillo added.
No Evidence of Benefit in Population Screening for Dementia
Despite efforts to improve timely detection of dementia, it is estimated as many as 50 percent of people with dementia do not receive a formal diagnosis or receive it after the dementia has progressed significantly. Some advocates and policy makers propose population screening for dementia as a way of increasing early detection, though this remains controversial. The relative costs and benefits are still unclear.
As reported at AAIC 2013, Brayne and colleagues conducted a systematic review of population screening studies. The researchers analyzed studies that looked at population screening either on its own or as a component of dementia intervention and compared outcomes with a routine pattern of care in the general population, among patients in general medical practice and among patients in community care. They identified eligible studies published by May 2012 through a broad search of the scientific literature.
The researchers found no evidence of the effect of screening on patient outcomes including cognitive, mental and emotional health, social function and planning. Based on the six studies that examined economic outcomes, the authors conclude that "substantial resources are required to screen for dementia"; costs depend on the age of the screened population, the properties of the screening instrument and the extent to which general practitioners are involved in follow-up assessments. The researchers were unable to identify any studies that looked at the potential harms caused by screening results, such as risk of depression, anxiety, stigma or loss of independence.
"We found no evidence that population screening would lead to better clinical or psychosocial outcomes, no evidence furthering our understanding of the risks it entails and no indication of its added value compared to current practice," said Brayne. "Policymakers should be very cautious about adopting population screening for dementia without any evidence of benefits or risks."
Alzheimer's Association Position on Dementia Screening in the Community
The Alzheimer's Association supports efforts that increase early detection and diagnosis of Alzheimer's disease by trained professionals in a medical setting — for example, the Association supports cognitive assessment as part of the Medicare Annual Wellness Visit, which is conducted in a controlled setting and administered by a trained clinician. At this time, the Alzheimer's Association does not support community-based memory screening.
The Association is working on many fronts to educate all stakeholders — individuals, families, physicians and policymakers — about the importance of early detection and early diagnosis and has developed a list of 10 Warning Signs of Alzheimer's Disease to assist with that effort. If individuals have experienced any of the following warning signs, it's important to seek a comprehensive diagnostic evaluation from a physician who is experienced in diagnosing and treating Alzheimer's.
Alzheimer's Association 10 Warning Signs of Alzheimer's Disease
1. Memory changes that disrupt daily life.
2. Challenges in planning or solving problems.
3. Difficulty completing familiar tasks at home, at work or at leisure.
4. Confusion with time or place.
5. Trouble understanding visual images and spatial relationships.
6. New problems with words in speaking or writing.
7. Misplacing things and losing the ability to retrace steps.
8. Decreased or poor judgment.
9. Withdrawal from work or social activities.
10. Changes in mood and personality.
For more information, visit: alz.org/10signs.
Misdiagnosis of Alzheimer's Disease Leads to Substantial Excess Costs
The misdiagnosis of Alzheimer's disease in Medicare patients who actually have vascular dementia or Parkinson's disease leads to substantial excess costs of care, according to a study conducted by Analysis Group Inc. and researchers from Eli Lilly and Company, and reported at AAIC 2013. They also found that those excess costs decline and eventually dissipate following a correct diagnosis.
The study authors analyzed administrative claims benefits for a random sample of Medicare beneficiaries and found that 17 percent of patients diagnosed with vascular dementia and 8 percent of patients diagnosed with Parkinson's disease had a prior incorrect diagnosis of Alzheimer's disease.
The researchers then retrospectively matched each previously misdiagnosed patient with a similar patient with no history of misdiagnosis, comparing the records of 2,088 matched pairs with vascular dementia and 2,058 pairs with Parkinson's. They found that during the time up to and including their confirmed correct diagnosis, the patients misdiagnosed with Alzheimer's disease incurred excess medical costs of up to $14,000 per year.
After the correct diagnosis, however, the excess costs dropped quickly. By the fourth year, on average, costs for previously misdiagnosed patients with both vascular dementia and Parkinson's disease were no higher than for patients who had never been misdiagnosed.
"Recent developments in technology have greatly improved our ability to properly diagnose patients with cognitive impairment," said Analysis Group's Noam Kirson. "Our results suggest that there are economic benefits to properly diagnosing — as early as possible — the cause of the cognitive impairment among patients with vascular dementia and Parkinson's disease. The U.S. healthcare system appears to be investing considerable resources due to misdiagnosis of Alzheimer's disease among these patients. Early diagnosis of other forms of dementia may help patients and providers avoid unnecessary costs and free up resources that could be used elsewhere."
(Note: Eli Lilly owns Avid Radiopharmaceuticals, which has a PET amyloid imaging compound that is FDA approved for visualization of amyloid plaque buildup in the brain and which can assist in ruling out Alzheimer's disease in those people with cognitive impairment.)
Experimental Imaging Agent Shows Promise in PET Detection of Tau in Alzheimer's
There are now substantial efforts underway to detect Alzheimer's earlier in the disease process — even before outward symptoms are noticeable or measurable — and also to identify changes happening in the brain that lead up to or effectively track the course of the disease. Tau pathology — tangles of misfolded tau protein in the brain — is a key biological marker of Alzheimer's disease, and one of the two well-recognized brains lesions characteristic of Alzheimer's disease; the other is amyloid plaques.
PET imaging agents for amyloid have been available to researchers for more than a decade, and one was approved by the FDA for clinical use in 2012. Similar compounds for imaging tau are just beginning to emerge, as shown in these next two reports from AAIC 2013.
A study by Hitoshi Shimada, M.D., Ph.D., of Japan's National Institute of Radiological Sciences and colleagues investigated the characteristics of [11C]PBB3, an experimental agent designed to bind to tau and make it visible on PET imaging in living people. Study participants, including people with Alzheimer's and age-matched healthy controls (more than 10 cases in both groups), were injected with an intravenous dose of [11C]PBB3 and given a PET scan. The study participants were also injected with [11C]PIB, an agent that binds to beta amyloid plaques, and scanned again.
PET imaging revealed high accumulation of [11C]PBB3 in different areas of the brain than [11C]PIB, as is appropriate in Alzheimer's. Distribution of the tau-binding agent in people with Alzheimer's extended to large areas of the brain; the distribution and degree of concentration correlated well with the participants' severity of disease.
"The results of this study support doing further research on [11C]PBB3 for detecting tau tangles in living persons," said Shimada. "Detecting the [11C]PBB3 binding agent throughout the brain may also show its ability to indicate the person's ‘stage' of dementia, because tau abnormalities are closely correlated to dementia severity. These are promising early results, and much more work is needed."
Case Study Supports Experimental PET Tau Imaging Agent in Alzheimer's disease
A radioactive tracer compound known as [F-18]-T808, an experimental agent for tau binding in PET imaging, was recently tested in 12 people, including eight with cognitive impairment. The death of one of the participants in the study (unrelated to the procedure) allowed for a post-mortem analysis of brain tissue compared to the results of a previous PET scan of his brain.
The male study participant, aged approximately 85 years, had a clinical diagnosis of likely Alzheimer's disease five years prior to the study. According to Hartmuth Kolb, Ph.D., senior vice president of research, Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, and colleagues, the [F-18]-T808 PET scan taken during the study suggested considerable tau pathology in most of the brain many of which are known to have tau buildup in Alzheimer's disease. The scientists found that a post-mortem analysis of the man's brain tissue was in agreement with the PET tau imaging results obtained with [F-18]-T808. In addition, the observed tau pathology appears to be consistent with the dementia experienced by the study participant.
"The observed pattern of [F-18]-T808 uptake in the subject's PET scan is very much consistent with what we found in the autopsy examination of tau deposition," Kolb said. "Though it is only one case study, these results support continued development of [F-18]-T808 and related PET tracers for identification of abnormal tau in the brains of people living with Alzheimer's disease."
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.
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- Carol Brayne, et al. There is no evidence supporting population screening for dementia – Reporting on a systematic review of costs and benefits. (Funder: Alzheimer's Society (UK))
- Noam Kirson, et al. Excess Costs Associated with Misdiagnosis of Alzheimer's Disease among U.S. Medicare Beneficiaries with Vascular Dementia or Parksinson's Disease. (Funder: Eli Lilly and Company)
- Hitoshi Shimada, et al. In vivo visualization of tau pathology in Alzheimer's disease patients by [11C]PBB3-PET. (Funder: Japan Advanced Molecular Imaging Program of the Ministry of Education, Culture, Sports, Science and Technology, Japan.)
- Hartmuth Kolb, et al. Image to Autopsy Correlation for Tau Imaging with [18F]-T808 (AV-680). (Funder: Avid Radiopharmaceuticals)
Proposal ID: 41164
Topic: Diagnosis and Prognosis; Clinical; Dementia
Presentation: Developing Topics II; Wednesday, July 17, 2013; 2:15-3:45 PM
There is no evidence supporting population screening for dementia – Reporting on a systematic review of costs and benefits
Presenting Author: Carol Brayne, Cambridge Institute of Public Health, UK.
Background: Despite over a decade of efforts to improve timely detection, as many as 50 percent of people with dementia still do not receive a formal diagnosis or receive it too late. Population screening may provide part of the solution. However, its relative costs and benefits are still unclear. We undertook a broad systematic review of population screening — here we report on the evidence pertaining to the clinical, psychosocial and economic outcomes.
Methods: Eligible studies included those looking at population screening either as a standalone or component of a dementia intervention compared with a routine pattern of care in general population or non-selected general practice or community care attendees. Models were included only in the review of economic outcomes. Relevant papers published by May 2012 were identified by unlimited database searches (including Medline, EMBASE, CINAHL, DARE) tailored to individual outcome categories. The AMSTAR tool guided the review process.
Results: We found no evidence of the effect of screening on patient outcomes such as cognitive, mental or emotional health, social function or planning. We didn't identify any studies looking at potential harms caused by the screening results (such as risk of depression, anxiety, stigma or independence). For economic outcomes (n=6), three primary studies reported on the direct cost per patient diagnosed; two related modeling studies compared a population screening scenario to other models of dementia care and one looked at screening in older drivers. These suggests that substantial resources are required to screen for dementia, which are determined by the age of the screened population, the properties of the screening instrument and the extent to which general practitioners are involved in follow-up assessments.
Conclusions: The pressure for faster diagnosis and for population screening is increasing despite the lack of effective early treatment. Yet we found no evidence that, if rolled out, population screening would lead to better clinical or psychosocial outcomes, no evidence furthering our understanding of the risks it entails and no indication of its added value compared to current practice. Policymakers should be cautious about the adoption of population screening for dementia without any evidence of benefits or risks.
Proposal ID: 41049
Topic: Social, Behavioral and Care Research; Early Detection
Presentation: Developing Topics II; Wednesday, July 17, 2013; 2:15-3:45 PM
Excess Costs Associated with Misdiagnosis of Alzheimer's Disease among U.S. Medicare Beneficiaries with Vascular Dementia or Parkinson's Disease
Presenting Author: Noam Kirson, Analysis Group Inc.
Background: Recent developments in diagnostic technology have improved the ability to rule out Alzheimer's disease (AD) in patients with cognitive impairment. This study examined potential economic benefits of ruling out AD among patients eventually diagnosed with vascular dementia (VD) or Parkinson's disease (PD), by estimating excess medical costs for those previously misdiagnosed with AD.
Methods: Retrospective analysis of de-identified administrative claims data for Medicare beneficiaries (5 percent random sample) identified two mutually exclusive patient cohorts with >2 claims for VD (ICD-9 CM: 290.4) or PD (332.x), without claims for other dementia types between or after their most recent VD/PD diagnoses. Within each cohort, patients were stratified based on prior diagnosis of AD in the three years preceding their first confirmed VD/PD diagnosis (defined as >2 claims with ICD-9-CM 331.0, or psychiatrist-diagnosed 290.0, 290.2, 290.3; patients with a single such claim were excluded). The index date was the first AD diagnosis for patients with prior AD and first confirmed VD/PD diagnosis for patients with no prior AD. Patients were required to have continuous Medicare coverage for =6 months pre-index (baseline) and >12 months following the first confirmed VD/PD diagnosis and were followed for up to four years post-index. Within each disease cohort, patients with prior AD were matched to similar patients with no prior AD using propensity score methods. Annual medical costs were compared between matched pairs in one year intervals, stratified by time to correct diagnosis.
Results: Approximately 17 percent of VD patients and 8 percent of PD patients had prior AD diagnoses. 2,088 matched pairs with VD and 2,058 with PD were analyzed. Post-matching, baseline characteristics were well-balanced for both cohorts. Patients previously diagnosed with AD incurred substantially higher medical costs in periods leading up to and including their confirmed VD/PD diagnoses, compared with their matched counterparts during the same timeframe. Excess costs declined — and eventually dissipated — following the confirmed VD/PD diagnoses (Figures 1 and 2).
Conclusions: This administrative claims data-based analysis suggests that misdiagnosis of AD among Medicare beneficiaries with VD or PD results in substantial excess costs. The change in excess costs trend following correct diagnosis suggests potential benefits from earlier rule-out of AD.
Proposal ID: 40964
Topic: Diagnosis and Prognosis; Neuroimaging; New Imaging Methods
Presentation: Developing Topics II; Wednesday, July 17, 2013; 2:15-3:45 PM
In vivo visualization of tau pathology in Alzheimer's disease patients by [11C]PBB3-PET
Presenting Author: Hitoshi Shimada, Molecular Imaging Center, National Institute of Radiological Sciences, Japan.
Background: Senile plaques and fibrillary tau inclusions are neuropathological hallmarks in Alzheimer's disease (AD). Tau pathology is considered to be closely related with neural dysfunction in AD and non-AD tauopathy, and could accordingly be an important target for both therapeutic intervention and diagnostic imaging. [11C]PBB3 has been recently developed as a tau imaging PET ligand, and showed high affinity and selectivity for tau deposits in our preclinical studies. The aim of the present study was to investigate characteristics of [11C]PBB3 in cognitively normal elderlies and patients with cognitive impairments.
Methods: Participants were patients with AD and age-matched healthy controls (HCs). A dose (about 10 mCi) of [11C]PBB3 was intravenously injected and sequential PET scans were performed for 70 minutes. Standardized uptake value ratio (SUVR) was calculated using the cerebellar cortex as reference region, and SUVR images were visually assessed in each subject. We also performed PET scan with a plaque-binding agent, [11C]PIB (about 10 mCi), for 70 minutes and three-dimensional T1-weighted MRI. Cerebral plaque depositions were estimated using SUVR images at 50 to 70 minutes after [11C]PIB injection. Parahippocampal grey matter volumes were estimated by voxel-based morphometry.
Results: All HCs were PIB-negative, and all AD patients were PIB-positive. SUVR images of [11C]PBB3-PET demonstrated high accumulation of [11C]PBB3 in the medial temporal cortex of all AD patients, in which binding of [11C]PIB was minimal. Distribution of [11C]PBB3 accumulation observed in AD patients extended to the entire limbic system and subsequently to the neocortex as a function of the disease severity. Interestingly, a subset of HCs also showed noticeable accumulation of [11C]PBB3 confined to the medial temporal cortex, and exhibited mild parahippocampal atrophy.
Conclusions: The present study supported the utility of [11C]PBB3-PET for detecting tau deposition in vivo, in light of distinct spatial distributions of [11C]PBB3 and [11C]PIB retentions in AD patients. Furthermore, the spread of [11C]PBB3 binding may reflect the dementia severity, resembling progression of Braak tau stages.
Proposal ID: 41130
Topic: Diagnosis and Prognosis; Neuropathology; Tau
Presentation: Developing Topics II; Wednesday, July 17, 2103; 2:15-3:45 PM
First Case Report: Image to Autopsy Correlation for Tau Imaging with [18F]-T808 (AV-680)
Presenting Author: Hartmuth Kolb, Avid Radiopharmaceuticals.
Background: [F-18]-T808 has been shown to have high affinity and selectivity for tau pathology in brain tissue sections from Alzheimer's disease (AD) patients (Zhang et al., 2012) and has recently been tested in 11 human subjects with promising results. Due to the death of one subject, an opportunity arose for an exploratory post mortem pathological analysis of brain tissue and comparison to the PET images.
Methods: The male subject (aged approximately 85 years) had been diagnosed with AD 5 years prior to this study and had a Mini-Mental State Exam score of 21 at the time of the PET study. The PET session consisted of a dynamic 0 to 50 minute PET scan after injection of 10 mCi (370 MBq) iv of [18F]-T808. Static PET images (30 to 50 minutes post injection) were used for analysis. Cerebellum uptake was used as a reference area. Approximately two weeks after imaging the patient died (unrelated to the procedure), allowing brain tissue sample collection and pathological evaluation for PHF-tau.
Results: The [18F]-T808 PET images revealed pronounced signal in the frontal, parietal, temporal lobes and hippocampus. Less pronounced tracer retention was observed in the posterior cingulate and the putamen. The cerebellum had low tracer retention. Post mortem staining for PHF-tau to date has been done with the fluorescent tau ligand T557 and was largely in agreement with the observed in vivo tracer distribution. Thus, tissue sections obtained from frontal, parietal and temporal lobe areas, and the hippocampus, appeared strongly positive for PHF-tau. The posterior cingulate and putamen displayed fewer tau tangles, and the cerebellum was negative.
Conclusions: The observed pattern of regional in vivo [F-18]-T808 uptake in the test subject is consistent with post mortem PHF-Tau staining. The considerable spread of tau pathology, observed in vivo and ex vivo, suggests an advanced Braak stage and is consistent with the dementia that the subject experienced. These results support [F-18]-T808 as a PET tracer for identification of PHF-tau in human brain. Additional work is planned to evaluate tau and ß-amyloid in the brain sections from this subject by immunostaining and autoradiography.
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