This paper shows that imaging of specific pathology with PET tracers provides diagnostic advantages over non-specific measures, such as atrophy on MRI and hypometabolism on FDG PET, that should lead to increased accuracy in the diagnosis of AD and much earlier diagnosis. However, there is room for substantial improvement in ligands for amyloid and tau imaging. FDDNP only showed a 9 percent increase in binding in AD compared to controls. Despite this small increase, the scan was able to distinguish all AD from controls due to very low variance in the groups and very low test-retest variation. This required a 2-hour scan that is not practical for widespread clinical application and it may be difficult for other groups to reproduce this level of precision. In contrast, C-11 PIB shows an 80-100 percent increase in cortical binding in AD compared to controls, and a simple delayed image of 20-30 minutes’ duration has been validated as an alternative to DVR. PIB images should be easier for clinicians to read. PIB is more specific, binding only to Aβ plaques, and therefore more...  Read more

This paper shows that imaging of specific pathology with PET tracers provides diagnostic advantages over non-specific measures, such as atrophy on MRI and hypometabolism on FDG PET, that should lead to increased accuracy in the diagnosis of AD and much earlier diagnosis. However, there is room for substantial improvement in ligands for amyloid and tau imaging. FDDNP only showed a 9 percent increase in binding in AD compared to controls. Despite this small increase, the scan was able to distinguish all AD from controls due to very low variance in the groups and very low test-retest variation. This required a 2-hour scan that is not practical for widespread clinical application and it may be difficult for other groups to reproduce this level of precision. In contrast, C-11 PIB shows an 80-100 percent increase in cortical binding in AD compared to controls, and a simple delayed image of 20-30 minutes’ duration has been validated as an alternative to DVR. PIB images should be easier for clinicians to read. PIB is more specific, binding only to Aβ plaques, and therefore more appropriate for assessment of therapies designed to alter Aβ levels. The disadvantage of C-11 PIB is the short half-life of the radioactive tag that requires each dose to be produced from a cyclotron immediately before each scan. Several F-18 tracers with properties similar to C-11 PIB are entering human trials. My group has studied 170 subjects with C-11 PIB including 50 with MCI. The greater dynamic range of PIB has allowed clear distinction within the MCI subjects of a group with normal uptake (35 percent of MCI subjects) with the rest predominantly falling into the lower range of AD subjects. This may allow prediction of those that will progress to AD from those who will not. It is generally accepted that 30-40 percent of persons given a diagnosis of MCI will improve or remain stable and that they are unlikely to have underlying AD. Longitudinal studies are underway to confirm or refute this proposal.

In summary, the paper by Small et al. is welcome news for those seeking a test to improve the accuracy and early diagnosis of AD. Improvements in tracer design should allow this technology to become a useful and widely available clinical tool.

View all comments by Christopher Rowe

In this study, the authors have used a somewhat unusual approach to recruit patients to take part in PET studies of Alzheimer disease (AD) and mild cognitive impairment (MCI). They have made advertisements about the study, including media coverage. From an initial sample of 737 volunteers, they included 25 AD, 28 MCI, and 30 controls in the study. All subjects who volunteered for the study described subjective memory problems. The 30 controls selected among the volunteering subjects have been found to have no measurable cognitive impairment. These 30 subjects would by many clinicians be called “subjects with subjective memory problems (subjective MCI),” but not considered to be controls.

Since some of the MCI patients were on cholinesterase inhibitor treatment, it might be possible that due to treatment effect they are not correctly classified as AD based on the cognitive tests.

There is a follow-up of 12 controls and four MCI subjects (two converted to AD) both with PET and cognitive testing. Since only two out of 28 MCI subjects are reported to convert to AD during 24...  Read more

In this study, the authors have used a somewhat unusual approach to recruit patients to take part in PET studies of Alzheimer disease (AD) and mild cognitive impairment (MCI). They have made advertisements about the study, including media coverage. From an initial sample of 737 volunteers, they included 25 AD, 28 MCI, and 30 controls in the study. All subjects who volunteered for the study described subjective memory problems. The 30 controls selected among the volunteering subjects have been found to have no measurable cognitive impairment. These 30 subjects would by many clinicians be called “subjects with subjective memory problems (subjective MCI),” but not considered to be controls.

Since some of the MCI patients were on cholinesterase inhibitor treatment, it might be possible that due to treatment effect they are not correctly classified as AD based on the cognitive tests.

There is a follow-up of 12 controls and four MCI subjects (two converted to AD) both with PET and cognitive testing. Since only two out of 28 MCI subjects are reported to convert to AD during 24 months, the conversion rate is very low.

The differences between the PET ligand FDDNP and PIB have been widely discussed since the initial papers on FDDNP (Shoghi-Jadid et al., 2002; Klunk et al., 2004) and concerns have been raised about the sensitivity of FDDNP. This is also illustrated in the paper of Small et al. where the authors report significant differences between control/MCI/AD, but the differences between changes in control and AD/MCI 5-10 percent should be compared to the robust differences between controls/AD/MCI with PIB of 40-70 percent (Klunk et al., 2004; Engler et al., 2006; Nordberg et al., 2006 IDAC Madrid 2006).

The authors report a significant difference between FDDNP binding in MCI versus AD patients. As illustrated in Figure 2 there is a broad variation in FDDNP binding in the MCI group overlapping both the AD and control group as well (see medial temporal cortex). The authors do not discuss whether there might be two groups of MCI patients—those who show FDDNP binding comparable with MCI, and those MCI patients with FDDNP binding comparable with AD. This is a phenomenon discussed for PIB binding in MCI (Price et al., 2005; Nordberg et al., ICAD Madrid 2006). The histopathological studies performed in one autopsy case with earlier FDDNP PET investigation showed abundance of especially immunoreactive tangles in the medial temporal regions. These observations may suggest that FDDNP might be a more sensitive marker for tangles than for amyloid plaques. If this is the case, we presently may have two PET ligands, namely PIB (amyloid plaques) and FDDNP (tangles), that could be quite useful for both the understanding of the time course of disease progression as well as for evaluation of new treatment strategies. The multi-tracer PET studies, which could also include tracers for inflammation processes and neurotransmitter function, would then provide a deeper understanding of the pathophysiological disease processes that we now, 100 years after Alois Alzheimer, are starting to understand in living AD patients.

I do not think we should discuss choosing between these two PET ligands. They probably are a good complement to each other and further evaluation is needed, especially now in subjects with hereditary forms of AD as well as in those with other forms of dementia. The PET ligands should also now be applied to the different types of anti-amyloid therapy that are being evaluated presently.

References:
Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang SC, Barrio JR. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002 Jan-Feb;10(1):24-35. Abstract

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. Abstract

Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, Nordberg A. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2856-66. Epub 2006 Jul 19. Abstract

Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP, Meltzer CC, DeKosky ST, Mathis CA. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab. 2005 Nov;25(11):1528-47. Abstract

View all comments by Agneta Nordberg

FDDNP-PET shows promise for monitoring plaque and tangle pathology in Alzheimer patients
Research advances on the molecular pathogenesis of Alzheimer disease (AD) have led to several drug candidates with potential disease-modifying effects, for example, secretase inhibitors and β amyloid immunotherapy. If any of these drugs prove to have a clinical effect, they are likely to have the best efficacy in the early phase of the disease, when the neuronal degeneration has not become too widespread. Thus, there is a great need for diagnostic tools, often called biomarkers, which will enable early and accurate diagnosis of AD. Especially, biomarkers allowing the identification of incipient AD already in patients with mild cognitive impairment (MCI) would be of great value.

However, considering the large variation in the distribution and severity of both neuropathological changes and neurochemical abnormalities among AD cases, it is unlikely that any single biomarker will fulfill the requirements of high enough sensitivity and specificity. Instead, combinations of...  Read more

FDDNP-PET shows promise for monitoring plaque and tangle pathology in Alzheimer patients
Research advances on the molecular pathogenesis of Alzheimer disease (AD) have led to several drug candidates with potential disease-modifying effects, for example, secretase inhibitors and β amyloid immunotherapy. If any of these drugs prove to have a clinical effect, they are likely to have the best efficacy in the early phase of the disease, when the neuronal degeneration has not become too widespread. Thus, there is a great need for diagnostic tools, often called biomarkers, which will enable early and accurate diagnosis of AD. Especially, biomarkers allowing the identification of incipient AD already in patients with mild cognitive impairment (MCI) would be of great value.

However, considering the large variation in the distribution and severity of both neuropathological changes and neurochemical abnormalities among AD cases, it is unlikely that any single biomarker will fulfill the requirements of high enough sensitivity and specificity. Instead, combinations of biomarkers, each reflecting different aspects of the neuropathological and neurochemical processes, will probably prove to be useful. Indeed, a number of promising diagnostic tools have to a different extent been validated for their capacity to identify AD early in the disease process, including the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phospho-tau (P-tau) and Aβ42; magnetic resonance imaging (MRI) measurements of hippocampal and entorhinal cortex atrophy; fluoro-deoxy-glucose (FDG) positron emission tomography (PET) measurements of regional abnormalities in glucose and oxygen metabolism; and visualization of β amyloid deposition using Pittsburgh Compound-B (PIB) PET [1].

In this paper, Gary Small and coworkers introduce a new PET method using the tracer 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to both plaques and tangles. In AD cases, FDDNP binds to cortical brain regions known to be affected by plaques and tangles.

In the study, data on FDDNP binding were presented as relative distribution volumes (DVR), which is the tracer distribution in the region of interest (ROI) divided by the distribution volume in the reference region (the cerebellum). In AD and MCI cases, approximately 10 percent higher DVRs were found in several cortical brain regions. Since the standard deviation (SD) within each diagnostic group was notably small, the estimated effect sizes (i.e., the difference between the group means divided by the pooled SD) were high, between 2.5 and 4.5.

The diagnostic accuracy of the method, evaluated by receiver operating characteristics (ROC) curves, was very high; 0.95 and 0.98 to differentiate MCI and AD from controls. Interestingly, ROC values for FDDNP were clearly higher than for either FDG-PET or MRI measurements of hippocampal volume.

Thus, the new FDDNP-PET shows great promise as a diagnostic tool for MCI and AD. FDDNP-PET may also be useful as a surrogate marker in clinical trials on the new type of drug candidates with disease-modifying potential, both in trials on drugs targeting Aβ deposition and tangle formation. Indeed, biomarker data from small clinical trials suggesting that a drug has positive effects on these pathogenic processes would be of great value to make a go/no-go decision for an expensive clinical trial with clinical improvement as the endpoint.

The research community will be waiting for future studies on the clinical usefulness of FDDNP-PET imaging. First of all, we need replication studies on prospective patients with lower dropout rates than in the present study, and also studies including cases with other dementia disorders such as frontotemporal dementia, Lewy body dementia, and Creutzfeldt-Jakob disease. It will also be interesting to see a direct comparison of the regional binding of the two ligands for plaques (PIB) and plaques and tangles (FDDNP). Further, since a recent study showed that all subjects, regardless of clinical status, with positive PIB binding had low CSF Aβ42 levels, and vice versa [2], it will also be interesting to learn how FDDNP binding correlates not only to CSF Aβ42 levels, but also to CSF T-tau and P-tau levels.

A last linguistic comment on the paper is that since the term “invasive” is defined as “puncture of the skin with entry of foreign material into the body as part of a diagnostic technique,” and FDDNP-PET is based on the injection of a radioactive substance into the body through an indwelling venous catheter, it may be considered unfortunate to claim FDDNP-PET as “a noninvasive method,” as in the conclusion of the Abstract. Nevertheless, FDDNP-PET is a promising new clinical tool for visualization of plaques and tangles directly in living patients, and is likely to provide useful diagnostic information in early AD.

References:
1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006 Jul 29;368(9533):387-403. Review. Abstract

2. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006 Mar;59(3):512-9. Abstract

View all comments by Kaj Blennow