clinical developments in amyloid pet imaging: research...

Clinical Developments in AmyloidPET Imaging: Research Updates CME/CE

Supported by independent educational grants from

Lilly USA, LLC.GE HealthcareNavidea BiopharmaceuticalsAlzheimer’s AssociationSociety of Nuclear Medicine and Molecular Imaging

View this activity online at:www.medscape.org/collection/amyloid

Pg.2

Clinical Developments in Amyloid PET Imaging: Research Updates CME/CE

This article is a CME/CE-certified activity.To earn credit for this activity visit:

www.medscape.org/collection/amyloid

CME/CE Released: 09/24/2014 ; Valid for credit through 09/24/2015

Target AudienceThis activity is intended for neurologists, radiologists, psychiatrists, geriatric psychiatrists, nuclear medicine physicians, nurse practitioners, and nurses.

GoalThe goal of this activity is to review recent data on amyloid positron emission tomography (PET) imaging in the diagnosis of Alzheimer’s disease and other dementias, with a focus on potential clinical applicability.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Review data on amyloid PET imaging in the diagnosis of Alzheimer’s disease and other dementias presented at the Society of Nuclear Medicine and Molecular Imaging annual meeting and the Alzheimer’s Association International Conference

Credits AvailablePhysicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

Nurses - 0.50 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accreditation StatementsFor Physicians Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing Medical Education for physicians.

Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

For Nurses Medscape, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Awarded 0.50 contact hour(s) of continuing nursing education for RNs and APNs; none of these is in the area of pharmacology.

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


Pg.3

Instructions for Participation and CreditThere are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test. Follow these steps to earn CME/CE credit*:1. Read the target audience, learning objectives, and author disclosures.

2. Study the educational content online or printed out.

3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile.

Hardware/Software RequirementsTo access Medscape Education users will need:

• A computer with an Internet connection.

• Internet Explorer 8.x or higher, the latest versions of Firefox or Safari, or any other W3C standards compliant browser.

• Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback.

• Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader.

Pg.4


Faculty and DisclosuresAs an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

AuthorsTammie L. S. Benzinger, MD, PhD Assistant Professor of Radiology and Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri

Disclosure: Tammie L. S. Benzinger, MD, PhD, has disclosed the following relevant financial relationships: Received grants for clinical research from: Avid Radiopharmaceuticals Dr Benzinger does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Benzinger does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Gil Rabinovici, MD Associate Professor of Neurology, University of California, San Francisco

Disclosure: Gil Rabinovici, MD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Avid Radiopharmaceuticals Dr Ravinovici does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Rabinovici does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Keith A. Johnson, MD Professor of Neurology and Radiology, Harvard Medical School; Director of Molecular Neuroimaging, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: Keith A. Johnson, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Biogen Idec; Avid Radiopharmaceuticals; GE Healthcare; Isis Pharmaceuticals, Inc.; Johnson & Johnson Research & Development, L.L.C.; Lilly

Received grants for clinical research from: Avid Radiopharmaceuticals; Lilly; Eisai Inc.; Merck & Co., Inc.; Navidea Biopharmaceuticals Dr Johnson does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Johnson does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


Pg.5

EditorKristin M. RichardsonScientific Director, Medscape, LLC

Disclosure: Kristin M. Richardson has disclosed no relevant financial relationships.

CME ReviewerNafeez Zawahir, MDCME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Nurse PlannerAmy Bernard, MS, BSN, RN-BCLead Nurse Planner, Medscape, LLC

Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

Pg.6


Clinical Developments in Amyloid PET Imaging: Research Updates CME/CE Tammie L. S. Benzinger, MD, PhD; Gil Rabinovici, MD; Keith A. Johnson, MDCME/CE Released: 09/24/2014 ; Valid for credit through 09/24/2015

Contents of This CME ActivityAll sections of this activity are required for credit.

Section 1. The Society of Nuclear Medicine and Molecular Imaging 2014 Annual Meeting Review new data on amyloid PET imaging in mild cognitive impairment, late-life depression, and post-stroke dementia. Tammie L. S. Benzinger, MD, PhD

Section 2. The 2014 Alzheimer’s Association International Conference Studies demonstrated that in appropriate scenarios, amyloid PET imaging can have a significant impact on patient care. Gil Rabinovici, MD

Section 3. The 2014 AAIC Alzheimer’s Imaging Consortium Studies investigated thresholds for PiB positivity, physical activity and AD, and vascular risk factors and AD. Keith A. Johnson, MD


Pg.7

I’m Tammie Benzinger, assistant professor of radiology at the Washington University School of Medicine in St Louis, Missouri. Welcome to this program on amyloid positron emission tomography (PET) imaging in the evaluation of Alzheimer’s disease (AD) and other dementias.

The goal of this program is to review new data on amyloid PET imaging and to assess the potential clinical application of these data. We will be discussing research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2014 Annual Meeting, which was held in St Louis, Missouri, and the 2014 Alzheimer’s Association International Conference (AAIC), which was held in Copenhagen, Denmark. I will focus on the SNMMI meeting.

These data should be considered preliminary until published in a peer-reviewed journal. I would also like to mention that this program will include a discussion of off-label treatment options. In addition, this program will include a discussion of investigational agents not approved by the US Food and Drug Administration (FDA) for use in the United States.

AD is a neurodegenerative disorder characterized by global atrophy with relative preservation of key areas of the brain, such as sensorimotor cortex. These 3 images were obtained at autopsy from a patient with AD. As you can see, the brain is greatly shriveled, with large gaps between the sulci. If you look at panels B and C, which are coronal sections, you can see that there is enlargement of the ventricles and loss of volume in the hippocampus, which is the main memory center.

The Society of Nuclear Medicine and Molecular Imaging 2014 Annual Meeting

Pg.8


AD has been characterized on the molecular level to have 2 key pathologies: neuritic plaques, such as the lesion on the left, and neurofibrillary tangles, which are the teardrop-shaped, dark lesions on the right. This is a silver stain (modified Bielschowsky method) of those lesions.

These lesions also have been have been characterized pathologically for many years with other agents, such as Congo red and, in the image shown, thioflavin. (Thiovlavin T stain viewed under ultraviolet light.) Thioflavins have the unique characteristic of being able to bind to these plaques and tangles, as shown in this image. Based on the molecular structure of thioflavin, multiple imaging agents for amyloid have been developed.


Pg.9

Models of AD progression have been developed demonstrating how AD begins long before clinical symptoms manifest. These models are based on cross-sectional research from sporadic cohorts and, more recently, studies in patients diagnosed with autosomal dominant AD.[1-3]

The first stage of the disease is amyloid deposition, which can be characterized by taking cerebrospinal fluid (CSF) samples and finding low levels of CSF β-amyloid 42 (Aβ42).This stage can also be characterized by imaging with amyloid PET.

The second stage of the disease is the neuronal injury phase, which can be seen as hypometabolic areas on a fluorodeoxyglucose (FDG) PET scan. This stage also can be assessed with volumetric magnetic resonance imaging (MRI), which will show changes associated with atrophy. At this stage of the disease, there are also findings of elevated tau in the CSF.

Pg.10


Cognitive changes do not begin until the final stages of the disease. Once someone has the cognitive deficits of AD, all these biomarkers will be positive.

Clinical imaging for dementia, our prior model, was based on more basic examination. In many clinical practices, the approach is to begin with a noncontrast head computed tomography (CT). The goal is to identify urgent or treatable conditions, such as in this patient with a subdural hematoma. Brain MRI can be used as the next stage of the assessment. This is a coronal image of a patient with normal-pressure hydrocephalus, as you can see by the enlarged ventricle centrally. Fluorodeoxyglucose PET has been available for many years for the workup of more complex cases, such as this patient with bilateral temporal lobe hypometabolism who was found to have an antibody syndrome resulting in limbic encephalitis.


Pg.11

There are, however, exciting new FDA-approved imaging options available in clinical practice, including quantitative MRI and amyloid PET imaging. Amyloid PET is positive, we anticipate, many years before dementia symptoms manifest. As shown in red, we see the FDG PET with hypometabolism in a pattern consistent with AD. The third image is a brain MRI showing hippocampal atrophy. These 3 scans were all obtained in 1 patient at our institution with dementia. This graphic helps you understand how we can fit imaging into the cycle of AD progression.

Currently, there are 3 FDA-approved agents for amyloid imaging in the United States: florbetapir, flutemetamol, and florbetaben. For many years, research in AD focused on Pittsburgh compound B, or carbon 11 PiB. The use of carbon 11 has been largely restricted to academic centers because of the short half-life of this tracer, which requires a cyclotron on site in order to produce it and perform the examination before the radioactivity has decayed. Also under investigation and reported at these meetings is the compound NAV4694.

Pg.12


Among the interesting developments presented at this year’s SNMMI meeting were potential applications of amyloid imaging in clinically complex situations similar to those we see every day in clinical practice. These include patients who have mild cognitive impairments or patients with subjective memory complaints. Patients with subjective memory complaints think that they have memory problems, but when they meet with their clinicians it is difficult to capture that belief clinically; they are not yet demented. Amyloid PET was also examined in more complicated cases, such as patients with depression and patients with stroke who develop dementia.

Brendel and colleagues studied 142 subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNII) Study.[4] These participants had longitudinal florbetapir amyloid PET scans as well as longitudinal clinical examinations. The investigators found that in participants with mild cognitive impairment (MCI), uptake in the mesial temporal lobe was higher in those who later converted to AD compared with participants with MCI who did not develop AD. They also found that longitudinal increases in amyloid PET were correlated with longitudinal cognitive decline. In other words, amyloid PET may be a promising tool to predict which patients with MCI will go on to develop AD dementia. Again, these findings are still in the research phase, but we are hopeful that further data will be forthcoming to help us better understand how amyloid PET may help us predict the conversion from MCI to AD.


Pg.13

In a related abstract, Ichise and colleagues examined 98 cognitively normal subjects who had been followed for up to 10 years previously with psychometric examinations.[5] Participants underwent florbetaben amyloid PET scans. When trajectories for cognitive decline, memory scores, and processing speed were determined, participants with higher levels of Aβ deposition had faster cognitive decline.

Rowe and colleagues studied 187 participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging who had not previously undergone imaging studies.[6] Forty-two participants with MCI, 11 with mild AD, and 134 healthy controls underwent flutemetamol amyloid PET scans. As expected, approximately 91% of the scans of AD subjects were positive. About half (55%) of the participants with MCI had a positive scan, and 22% of healthy controls had a positive amyloid PET scan.

The investigators further examined the healthy controls and asked if they had subjective memory complaints (nothing that could be detected by a clinician, but the participant believed he or she had a memory problem). Thirty-three percent of the healthy controls with subjective memory complaints had a positive scan, while only 7% of healthy controls without subjective memory complaints had a positive scan.

Pg.14


More complex clinical situations, such as late-life depression and post-stroke dementia were also examined at the meeting.

Brendel and colleagues examined 371 ADNII participants with MCI who underwent assessment for depression and received florbetapir PET scans.[7] Investigators found that elevated florbetapir uptake in the frontal cortex and posterior cingulate gyrus was present in patients with depression. The most significant association was found between patients who were the most depressed and those with frontal amyloid burden.


Pg.15

What do these findings suggest? Currently, approval for amyloid imaging agents in the US is limited to patients who have clear symptoms of dementia. It looks as if research is suggesting that there may be a potential future role for these agents in the evaluation of earlier phases of dementia. However, at this point, the findings may be most useful as we determine which cohorts would be best suited for clinical trials.

When we look at complex scenarios such as depression and stroke, more research is needed to determine if amyloid PET imaging would be helpful. In the case of depression, it appears that a good number of older patients with depression probably do have positive amyloid scans. However, when we look at the example of stroke, not as many patients with dementia after stroke had an AD pattern on an amyloid PET scan.

We have come a long way. We have many exciting, new options, and we look forward to what the future holds for the field.

Thank you for your attention. Please continue to the next presentation in the program.

This transcript has been edited for style and clarity.

In a study of post-stroke dementia, 37 participants with stroke underwent amyloid PET scan.[8] However, in this study, there was no association between post-stroke dementia and amyloid positivity.

Pg.16


The 2014 Alzheimer’s Association International Conference

Hello. I’m Gil Rabinovici, associate professor of neurology at the University of California, San Francisco, Memory and Aging Center. I will be discussing data presented at the 2014 AAIC, which was held in Copenhagen, Denmark.

Before we begin, it is important to remember that these data should be considered preliminary until published in a peer-reviewed journal. I would also like to mention that this program will include a discussion of investigational agents not approved by the FDA for use in the US.

Alzheimer’s disease is the leading cause of dementia. It affects an estimated 5,000,000 Americans, and the prevalence of the disease is rising as the population ages. An early and accurate diagnosis will be critical in implementing emerging disease-specific therapies. However, we have learned from clinicopathologic studies that a clinical diagnosis, even when made by experts, has limited accuracy vs the gold standard of neuropathology. An evaluation of the relationship between clinical and pathologic diagnosis in more than 900 patients seen in AD centers in the US showed that a clinical diagnosis of AD had only 70% sensitivity and specificity compared with the pathologic diagnosis.[9] As clinicians we can–and we must–do better as we import new therapies.


Pg.17

Amyloid imaging could improve diagnostic accuracy because it detects neuritic plaques, which are a core feature of AD pathology. It is important, however, to consider that detecting amyloid in the brain is not synonymous with diagnosing AD. Brain amyloid can also be found in non-AD dementias, for example Lewy body disease or amyloid angiopathy. Furthermore, approximately 25% of cognitively normal older adults have significant amyloid in their brain but no cognitive symptoms. An amyloid PET scan needs to be interpreted in the context of a comprehensive clinical evaluation.

The first PET tracer specific for amyloid plaques that was successfully implemented and researched was 11C- PiB. This tracer is still considered the gold standard, but it has a very short half-life, only 20 minutes, which limits its use to research centers. There are a number of amyloid imaging agents labeled with Fluorine 18 (18F), which has a 110-minute half-life. This is the same half-life as the radiolabel for FDG PET, which is, of course, used extensively in medicine.

The 18F-labeled amyloid imaging tracers that have been developed thus far include florbetapir, flutemetamol, florbetaben, and NAV4694. Three of these tracers, florbetapir, flutemetamol, and florbetaben, have been approved in the United States and Europe for clinical use. A number of studies presented at the AAIC addressed the diagnostic utility of these tracers.

Pg.18


The first study I will discuss is “A Negative Florbetaben PET Scan Reliably Excludes Amyloid Pathology as Confirmed by Histopathology.”[10] One of the most important steps in validating an amyloid imaging tracer is to prove that the signal during life corresponds to amyloid found postmortem. John Seibyl, MD, on behalf of the Florbetaben Study Group, presented data validating the accuracy of antemortem florbetaben PET vs postmortem assessment of amyloid. Seibyl and colleagues studied 74 patients who were at the end of life and under hospice care. These individuals had PET scans during life, and after death brain autopsy was performed, on average approximately 10.8 months after the PET scan. The scans were read by 3 raters who were blinded to clinical information, and the majority read had a 98% sensitivity and an 85% specificity for significant amyloid burden at autopsy. The sensitivity and specificity of individual raters were very similar to the majority reads.

An important caveat is that end-of-life patients may not represent the spectrum of pathology that would be seen in a memory clinic, where presumably patients would be scanned at a much earlier disease stage. Nevertheless, overall the study showed that florbetaben PET had a high accuracy in detecting amyloid; this study ultimately led to regulatory approval of this tracer for clinical use.

The next study I will discuss is “The Prevalence of Aβ PET Positivity Across Dementia Syndromes.”[11] In this study, Ossenkoppele and colleagues from the VU University Medical Center in Amsterdam, The Netherlands, tabulated the rates of amyloid PET positivity in approximately 2000 patients with a variety of dementia syndromes and approximately 3000 controls. This represented data studied across more than 50 sites around the world. The goal was to determine the optimal scenarios in which an amyloid PET scan can aid in differential diagnosis.


Pg.19

The researchers identified 4 scenarios in which amyloid PET had the greatest diagnostic utility. The first was in the differential diagnosis of early-onset dementia. This makes a great deal of sense because we know that clinical diagnosis is especially inaccurate in this group of patients, and the overall prevalence of amyloid in younger individuals is lower than in older individuals. Therefore, the scan is very helpful in ruling AD in or out in younger individuals.

The second indication identified was to support the clinical diagnosis of AD dementia in APOE-ε4 non-carriers older than age 70 years. This, again, converges nicely with data from 2 large clinical trials in which the rate of amyloid negativity in people who were diagnosed with AD dementia but lacked the APOE-ε4 risk allele was about 35%.[12,13] Again, clinical certainty is lower in this scenario, and an amyloid PET scan can help support a clinical diagnosis.

The third scenario was to identify mixed pathology in elderly patients with non-AD dementia.

The fourth and final scenario was to detect the underlying neuropathy causing corticobasal syndrome, a heterogeneous clinical and pathologic entity that is caused by AD approximately 25% of the time.

I would like to point out that these indications also match nicely with the Appropriate Use Criteria for Amyloid PET, which were published in 2013.[14,15]

Pg.20


The next study is “Imaging Mild Cognitive Impairment with a Second Generation Tracer.”[16] Nair and colleagues from the Quincy Medical Center in Quincy, Massachusetts, examined the reliability of visual reads of NAV4694 PET scans collected at their site as part of an industry-sponsored longitudinal study of patients diagnosed with MCI. This is an incredibly important clinical population when thinking about early detection of AD, and in practice, amyloid PET scans will be interpreted visually, so inter-rater reliability is important to establish.

In this study, 2 expert raters showed 100% agreement in interpreting 12 scans, including 8 positive scans and 4 negative scans, so these preliminary results show very high inter-rater reliability. A clinical trial investigating the prognostic value of NAV4694 in predicting clinical decline in patients with MCI is ongoing and will be important when we think about clinical applications of amyloid PET.[17]

The next study is “Diagnostic Value of Amyloid Imaging in Early-Onset Dementia.”[18] Zwan and colleagues from the VU University Medical Center in Amsterdam assessed the impact of flutemetamol PET scans on the diagnosis and management of 80 early-onset dementia patients at their center who presented with the dementia syndrome before age 70 years. The investigators found that the PET scan results were discordant with the pre-PET clinical diagnosis in 25% of patients. These PET scan results led to a change in diagnosis in 20% of patients and to changes in management in more than half of patients. These management changes included modifications in AD medications, such as starting or stopping cholinesterase inhibitors and memantine, and adding diagnostic testing or discontinuing planned, additional diagnostic testing. Changes in nonpharmacologic care plans were also made, including referral to other providers.


Pg.21

The last study that I am going to discuss is “Amyloid PET Has Greater Clinical Impact Than FDG PET in the Differential Diagnosis of Alzheimer’s Disease and Frontotemporal Dementia.”[19] Ghosh and coworkers from the University of California, San Francisco, directly compared the clinical impact of florbetapir and FDG PET scans in the assessment of 50 patients with suspected AD or frontotemporal dementia (FTD). While FDG PET is reimbursed by Medicare for this indication, previous work has suggested that amyloid PET may be more accurate in differentiating these 2 diseases.

In this study, all patients had amyloid and FDG PET scans. Results for each patient were sequentially disclosed to 2 behavioral neurologists in a balanced design. Amyloid results were disclosed first to one of the physicians, and then the FDG PET scan results were disclosed. Conversely, the second physician received the FDG scan results first and the amyloid results second. Prior to receiving amyloid or FDG PET results, and also following disclosure of each of the scans, clinicians filled out case report forms about their current diagnosis and management plan.

In this study, florbetapir led to a change in diagnosis in 27% of cases, significantly higher than the 15% for FDG. Furthermore, changes in patient management were more common after florbetapir: 32% of the time compared with FDG 13% of the time, also significantly different. The investigators concluded that amyloid PET may be the PET scan of choice in differentiating AD and FTD.

Pg.22


To summarize, studies presented at AAIC demonstrated that amyloid PET is accurate, can be reliably read, and, in appropriate scenarios has a significant impact on patient care. Again, it is important to emphasize that the scan needs to be interpreted in the context of a comprehensive clinical evaluation, not just considered in isolation. Patient access to amyloid PET has been limited due to lack of reimbursement. Third-party payors, including Medicare, want to see evidence that the scans affect patient outcomes, not just diagnosis. Such studies are ongoing or in preparation.

As amyloid PET is poised to enter the clinic, a new generation of PET tracers that target the second key pathology in AD, neurofibrillary tangles composed of the tau protein, are being applied in research settings. I think that the combination of amyloid and tau PET will greatly advance our understanding of aging and AD and, ultimately, these breakthroughs in diagnostics should facilitate the development of treatments for this devastating disease.

I would like to thank you for your attention. Please continue to the next presentation in this program.



Pg.23

The 2014 AAIC Alzheimer’s Imaging Consortium

I’m Keith Johnson, director of molecular neuroimaging at Massachusetts General Hospital and professor of radiology at Harvard Medical School in Boston, Massachusetts. I’ll be discussing data presented at the Alzheimer’s Imaging Consortium, a preconference associated with the 2014 AAIC.

I would like to point out that the Imaging Consortium received commercial support. I would also like to mention that these data should be considered preliminary until published in a peer-reviewed journal. Also, this program will include a discussion of investigational agents not approved by the FDA for use in the United States.

I will briefly summarize 4 presentations from the meeting that I think have general interest.

The first presentation is titled “Vascular Risk Factors Impact Cognition Independent of PiB PET and MRI Measures of Alzheimer’s Disease and Vascular Brain Injury.”[20] In this work, first author Charles DeCarli, MD, related cognition to amyloid and structural imaging in 65 predominantly nondemented older individuals, 79% of whom had vascular risk factors such as diabetes, hypertension, and elevated cholesterol. The authors found that vascular risk factors were predictive of baseline executive function even when amyloid PET, MRI atrophy, and white matter abnormality measures were included in the models. These findings support the idea that executive function deficits are related to modifiable risk factors for impairment, regardless of amyloid burden or structural white matter damage.

Pg.24


The second study is titled “Existing Thresholds for PiB Positivity are Too High.”[21] In this work, Villeneuve and colleagues explored the earliest detectable signal of amyloid using PET data from 152 cognitively normal older adults. They found that the PiB PET signal, representing Aβ, emerged in the medial frontal cortex and then spread to the precuneus and to lateral frontal and parietal lobes. Amyloid had already accumulated in a large fraction of these normal older individuals who were below the commonly used cutoffs. The significance of lower levels of positive signal, therefore, needs to be thoroughly evaluated. These signals may represent accumulation that is clinically meaningful or prognostic.

The third presentation is titled “Physical Activity Modifies Alzheimer Biomarkers in Preclinical Alzheimer’s Disease: Evidence from the Wisconsin Registry for Alzheimer’s Prevention.”[22] In this work, Okonkwo and colleagues compared self-reported current physical activity with cognitive performance and Alzheimer biomarkers in more than 300 normal older individuals. They found that physical activity, measured as current activity, reduced age-related hippocampal atrophy, age-related amyloid deposition, and age-related glucose hypometabolism. In other words, 3 key biomarkers of AD pathology were found to be modified by current levels of physical activity.


Pg.25

In the fourth study, “Imaging of Tau Pathology in Patients with Non-Alzheimer’s Disease Tauopathies by [11C]PBB3-PET,”[23] investigators from Japan reported PET data from 10 patients with progressive supranuclear palsy and 5 patients with corticobasal syndrome and compared them with data from 18 older normal controls. They found that in progressive supranuclear palsy, the tau tracer binding was elevated in globus pallidus, putamen, thalamus, midbrain, pons, and perirolandic cortex. In contrast, the corticobasal syndrome patients showed high binding in perirolandic and premotor cortices, subthalamus, and midbrain. These data support the potential utility of this new technology, tau PET, in non-AD degenerative disorders, given the reported anatomic distribution of PET ligand binding in AD, which appears to be quite different from what was seen in these 2 non-AD neurodegenerative conditions.

In summary, the Alzheimer’s Imaging Consortium revealed progress in many different directions, which points to an evolving utility for imaging in clinical practice as it relates to aging and dementia.


This article is a CME/CE certified activity. To earn credit for this activity visit: www.medscape.org/collection/amyloid

Pg.26


REFERENCES 1. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010; 9:119-128. 2. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280-292. 3. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795-804. 4. Brendel M, Högenauer M, Delker A, Bartenstein P, Rominger A. Longitudinal amyloid PET in mild cognitive impaired patients . J Nucl Med. 2014;55:193.5. Ichise M, Gu Y, Razlighi Q, et al. The presence of brain amyloid is preceded by accelerated cognitive decline in non-demented older adults: results from a multi-ethnic population. J Nucl Med. 2014;55:189.6. Rowe C, Doré V, Bourgeat P, et al. Higher Aß burden in subjective memory complainers: a flutemetamol sub-study in AIBL. J Nucl Med. 2014;55:191.7. Brendel M, Kalinowski E, Delker A, Bartenstein P, Rominger A. Subsyndromal late life depression is associated with amyloid accumulation in mild cognitive impairment. J Nucl Med. 2014;55:87.8. Daerr S, Wollenweber F, Brendel M, et al. Determinants of dementia after stroke: Amyloid PET findings. J Nucl Med. 2014;55:1843.9. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol. 2012;71:266-273. 10. Stephens A, Barthel H, Ishii K, et al. A negative florbetaben PET scan reliably excludes amyloid pathology as confirmed by histopathology. Presented at the Alzheimer’s Association International Conference®; July 12-17, 2014; Copenhagen, Denmark.11. Ossenkoppele R, Jansen WJ, Scheltens P, van Berckel B, Visser PJ. The prevalence of Aß PET positivity across dementia syndromes. Presented at the Alzheimer’s Association International Conference®; July 12-17, 2014; Copenhagen, Denmark.12. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014; 370;322-333. 13. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311-321. 14. Johnson KA, Minoshima S, Bohnen NI, et al; Alzheimer’s Association; Society of Nuclear Medicine and Molecular Imaging; Amyloid Imaging Taskforce. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9:e1-e16.

15. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. J Nucl Med. 2013;54:476-490. 16. Nair AK, Brooks H, Feijo F, et al. Imaging mild cognitive impairment with a second generation tracer NAV4694 has near perfect inter-rater reliability. Presented at the Alzheimer’s Association International Conference®; July 12-17, 2014; Copenhagen, Denmark.17. ClinicalTrials.gov. Beta-amyloid imaging with [18F] NAV4694 positron emission tomography (PET) in predicting progression to Alzheimer’s disease (AD) in subjects with mild cognitive impairment (MCI) (NAV4-04). NCT01812213.18. Zwan MD, Bouwman FH, Van der Flier WM, Lammertsma A, van Berckel b, Scheltens P. Diagnostic value of amyloid imaging in early onset dementia. Presented at the Alzheimer’s Association International Conference®; July 12-17, 2014; Copenhagen, Denmark.19. Ghosh PM, Madison C, Santos M, et al. Amyloid PET has greater clinical impact than FDG PET in the differential diagnosis of AD and FTD. Presented at the Alzheimer’s Association International Conference®; July 12-17, 2014; Copenhagen, Denmark.20. DeCarli C, Mungas D, Carmichael OT, et al. Vascular risk factors impact cognition independent of PIB PET and MRI measures of Alzheimer’s disease and vascular brain injury. Presented at the Alzheimer’s Association International Conference® Imaging Consortium Preconference; July 12, 2014; Copenhagen, Denmark.21. Villeneuve S, Madison C, Ayakta N, et al. Existing thresholds for PIB positivity are too high. Presented at the Alzheimer’s Association International Conference® Imaging Consortium Preconference; July 12, 2014; Copenhagen, Denmark.22. Okonkwo O, Oh J, Schultz S, et al. Physical activity modifies Alzheimer biomarkers in preclinical Alzheimer’s disease: evidence from the Wisconsin registry for Alzheimer’s prevention. Presented at the Alzheimer’s Association International Conference® Imaging Consortium Preconference; July 12, 2014; Copenhagen, Denmark.23. Shinotoh H, Shimada H, Hirano S, et al. Imaging of tau pathology in patients with non-Alzheimer’s disease tauopathies by [11C]PBB3-PET. Presented at the Alzheimer’s Association International Conference® Imaging Consortium Preconference; July 12, 2014; Copenhagen, Denmark.

ABBREVIATIONSAβ42 = β-amyloid 42 AAIC = Alzheimer’s Association International Conference AD = Alzheimer’s disease ADNII = Alzheimer’s Disease Neuroimaging Initiative AIBL = Australian Imaging, Biomarkers and Lifestyle APOE = apolipoprotein E CSF = cerebrospinal fluid CT = computed tomography FDG = fluorodeoxyglucose FTD = frontotemporal dementia MCI = mild cognitive impairment MRI = magnetic resonance imaging PET = positron emission tomography 11C-PiB = carbon 11 Pittsburgh compound B SNMMI = Society of Nuclear Medicine and Molecular Imaging

clinical developments in amyloid pet imaging: research...

Documents