There are several reasons why this paper is highly cited. The development of imaging technology and especially of Positron Emission Tomography (PET) as a tracer technology has been demonstrated in several studies focusing on various aspects of neurofunctions. PET as a tracer technology with many types of tracer molecules allows the fast development of molecular imaging tools for various applications in humans. The impact of this technology is at present significant in several fields of diagnosis in areas such as cancer, cardiology, and neurology. In the paper "Imaging brain amyloid in Alzheimer’s disease..." another type of tracer than the ones previously developed is described. In the past several studies describing binding related to receptors, enzymatic functions or reuptake systems have been successfully applied in healthy controls and in patients. In the present study, patients diagnosed with Alzheimer's disease were investigated and the amyloid-related binding was shown.

Since the amyloid theory is a key theme in the development of new treatments for Alzheimer’s disease, this new possibility of imaging amyloid load is interesting and the development of a PET-tracer to visualize amyloid or amyloid-related processes in human brains might have a significant value. The results presented in this paper are interesting and may lead to a faster development process for new treatments to allow the efficacy-related measures of such treatments in humans.

Today, the confirmation of the diagnosis of Alzheimer’s disease given by a clinical physician is only possible after autopsy. A pathologist opens the brain, cuts it in small slices and, using a special staining technique, the presence of a substance (amyloid) that is characteristic of Alzheimer’s disease can be detected. We have succeeded in showing the presence of this substance in the living brain. This opens up a possibility to differentiate patients with Alzheimer’s from patients with other diseases and thus offers the possibility of early treatment. We can now follow up the effect of new drugs that might have an impact on the harmful substance amyloid.

  Why did I become involved in this project?

For a long time, I have been working with PET to develop tools to explore neurodegeneration (Engler H, Lundberg PO, Ekbom K, Nennesmo I, Nilsson A, Bergström M, Tsukada H, Hartvig P, Långström B; (2003): Multitracer study with positron emission tomgraphy in Creutzfeldt-Jacobs disease, Eur.J. Nucl. Med. 30:85-95, 2003, and we have been involved in many studies in the field of degeneration of motor neurons (Ekesbo A, Rydin E, Torstenson R, Sydow O, Långström B, Tedroff J : Dopamine autoreceptor function is lost in advanced Parkinson’s disease, Neurology 52:120-5, 1999, and for at least 15 years we have been exploring PET and PET-tracers as a tool in Alzheimer’s research. In collaboration with Professor Agneta Nordberg at the Karolinska Institute, we have been involved in various studies related to the acetylcholinergic system—Nordberg, A, Almkvist, O., Amberla, K, Basun, H, Corder, B, Ebendal, T, Gottfries, C-G, Hartvig, P, Hellström-Lindahl, E, Jelic, V, Jönhagen, M, Lannfelt, L, Lehman, W., Långström, B, Lundqvist, H, Meurling, L, Meyerson, B, Olson, L, Seiger, Å, Valind, S, Viitanen, M, Wahlund, L-O, Winblad, B. Responders and non-responders to tacrine, ondansetron and NGF treatment in Alzheimer patients as evaluated by positron emission tomography and APOE genotype. In: Alzheimer's Disease Biology: Diagnosis and Therapeutics, Eds. K Iqbal, B Winblad, T Nishimura, M Takeda, HM Wisniewski. John Whiley and Sons, Chichester, 647-653, 1997; Nordberg A, Jelic V, Arnaiz E, Långström B, Almkvist O Brain functional imaging in early and preclinical Alzheimer´s disease. In K. Iqbal SSSBW (ed): "7th Intl. AC. Conf." pp 153-164, 2001, and since the middle of the 90’s the imaging of amyloid and amyloid plaque has been targeted. During 1998, a discussion of potential collaborations with Professors Klunk and Mathis in Pittsburgh was started, since they had at that time developed potential lead tracers for the amyloid application. Simultaneously, in Uppsala, we had been in deep discussions with the Swedish Medical Product Agency (SMPA) regarding a concept called the PET-microdosing, which allowed a reduced risk assessment when developing new PET-tracers used in very low amounts. Based on the fact that PET-tracers are produced in tiny amounts, we have been arguing that this should have an impact on how to perform risk assessments—Bergström M, Grahnen A, Långstrom B: PET-microdosing, a new concept with application in early clinical drug development, Eur. J. Pharmacol 2003:357-366. So, at a meeting in Washington with Professor Klunk—held in connection with my trip to the United States in 2001—I was told that he and Professor Mathis had developed an interesting lead tracer based on a bensothiazol structure which was a new chemical entity in man. It was thus a nice test case to bring this lead tracer to humans testing our PET-microdosing concept which we had earlier discussed with the SMPA.

After performing toxicology and safety pharmacology testing according to this concept, we went ahead and performed the study in humans after a required preclinical safety validation as described in the microdosing paper.

We assume that in the next few years imaging data will tell us more regarding the amyloid theory and that we will eventually achieve success in early diagnosis and realize its value as a tool in the development of new drugs. Most likely 18F-labelled PIB analogues will be available for wider use.

Furthermore the microdosing concept is now gaining in recognition. In 2004, EMEA presented a position paper on the matter and it appears likely that the FDA will also present a position paper on this same subject at some time in the near future.