NEUROLOGICAL REVIEW Imaging Technology for Neurodegenerative Diseases Progress Toward Detection of Specific Pathologies Chester A. Mathis, PhD; William E. Klunk, MD, PhD; Julie C. Price, PhD; Steven T. DeKosky, MD dvances in neuroimaging over the past 2 decades are products of breakthroughs in imaging technology, developments of more powerful computers and image- processing software, and expanding knowledge in basic and clinical neuroscience. In addition to the insights into normal brain structure and function that such methods Aprovide and the information that can be gained from disease-related changes in structure and func- tion, the promise of achieving diagnostic specificity through neuroimaging lies with the potential identification of pathognomonic proteins. Recent advances in imaging ␤-amyloid plaques, one of the hallmarks of Alzheimer disease, offer such a technological breakthrough and the possibility for more efficient assessment of antiamyloid interventions as well as specific noninvasive diagnos- tic capabilities. Arch Neurol. 2005;62:196-200 In the last several decades of the 20th cen- and other pathological disturbances. Tech- tury and the first several years of the 21st, niques for the rapid assessment of blood research and the clinical application of flow advanced functional imaging and the neuroimaging have proceeded at a dizzy- localization of brain activity or function. ing and accelerating rate. Structural im- Magnetic resonance spectroscopy contin- aging was initially limited to skull and ues to develop as another method for the spine radiographs and subsequently to in- noninvasive assessment of brain metabo- ference about what was happening in the lism in development, aging, and disease. brain by analyzing the patterns of arte- The development of positron emis- rial, capillary, and venous blood flow on sion tomography (PET) has followed a cerebral angiography. The advent of the similar rapid evolution since implemen- computed tomography scan in the 1970s tation in the 1970s. These advances in- allowed visualization of brain paren- clude improved detector systems, in- chyma for the first time, and advances in creases in computer processing power and hardware, computer power, and imaging programs to use such power, and ad- programs led to improved resolution. Mag- vances in radiochemistry. These ad- netic resonance imaging added to the vances in turn led to breakthroughs in our bounty of new structural imaging tech- understanding of cerebral blood flow, en- niques in the 1980s and also progressed ergy metabolism, and neurotransmitter through increased imaging resolution and function in humans both with and with- new sequences that led to better visual- out neurological disease. Patterns of ab- ization of white matter, water diffusion, normalities in blood flow or glucose me- tabolism, although nonspecific, have Author Affiliations: Departments of Neurology, Psychiatry, and Radiology, provided significant diagnostic aid in Alz- University of Pittsburgh and Western Psychiatric Institute and Clinic, Pittsburgh, Pa. heimer disease, dementia with Lewy bod- Financial Disclosure: GE Healthcare (formerly Amersham Health) (Chalfont 1 St. Giles, United Kingdom) provided research grant support to the University of ies, and frontotemporal dementia. The Pittsburgh and entered into a license agreement with the University of Pittsburgh ability to devise imaging ligands that bind based on the technology described in this article. Drs Klunk and Mathis are to central nervous system enzymes, re- coinventors of Pittsburgh Compound B and, as such, have a financial interest in ceptors, transporters, or other compo- this license agreement. nents of neurotransmitter systems has been (REPRINTED) ARCH NEUROL / VOL 62, FEB 2005 WWW.ARCHNEUROL.COM 196 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 the special province of PET. Alterations in these PET H3C HO markers over the course of time has aided diagnosis and S CH3 S H added information about the progression of disease. N N + N CH N Recently, PET research has begun to focus on the abil- 3 CH3 CH ity to image the abnormal proteins associated with spe- 3 cific neurodegenerative diseases. The ability to image the Thioflavin T PIB amyloid plaques and neurofibrillary tangles of Alzhei- mer disease (AD), the Lewy bodies of Parkinson disease Figure 1. Derivation of Pittsburgh Compound B (PIB) from the fluorescent or dementia with Lewy bodies, or other pathognomonic histochemical dye thioflavin T. proteins would enable unprecedented accuracy of diag- nosis; it would also allow staging of disease and a basis ing affinity of the derivatives for A␤, deletion of the charge for the efficient evaluation of therapeutic interventions from thioflavin T dramatically increased the binding af- to halt the accumulation of, decrease the levels of, or re- finity of the derivatives for A␤. Further derivatization of move abnormal proteins. these neutral analogues of thioflavin T (termed benzo- For amyloid, the potential benefits of a pathology- thiazole anilines) indicated that substitution of the driven imaging approach are the following: 6-methyl group with a 6-hydroxyl group provided a po- tent A␤ ligand with excellent in vivo pharmacokinetic v Improvements in early diagnosis and the possibil- imaging properties.3 This 6-hydroxyl–substituted ben- ity of a presymptomatic diagnostic biomarker, depend- zothiazole aniline is known as Pittsburgh Compound B ing on the time course of amyloid deposition (PIB) (Figure 1). When radiolabeled with carbon 11, v Improved understanding of the natural history of PIB provides a radioligand for PET imaging studies of A␤ amyloid deposition and insights into the pathophysiol- in the brains of living human subjects.4 Pittsburgh Com- ogy of AD, along with a potential tool to further evalu- pound B retains the highly fluorescent properties of its ate the amyloid cascade hypothesis parent, thioflavin T, and has been used to image A␤ in v The capability to directly measure the effects of newly the brains of living transgenic mice using multiphoton developed antiamyloid therapies (eg, secretase inhibi- microscopy techniques.5 tors, immunotherapy, and “plaque breakers”) Critical to the demonstration of the binding targets The ability to directly measure a pathological change of benzothiazoles were binding assays that used homog- believed to be intimately related to the pathophysiology enates of postmortem brain because these assays could of the disease might have advantages over less specific be performed using the low nanomolar concentrations structural or metabolic measures in all of these areas, but of amyloid probe that are attainable during in vivo PET the advantage is clearest in the ability to directly mea- studies.6 In brain areas known to contain high concen- sure the efficacy of antiamyloid therapies. Toward this trations of A␤ deposits (eg, the frontal and temporal cor- end, our group set out to develop PET tracers specifi- tex), tissue homogenate studies showed greater than 10- cally for the ␤-amyloid peptide (A␤) in plaques and cere- fold more binding of benzothiazole compounds to AD brovascular amyloid in AD and related conditions. Our brain compared with age-matched control brain. In con- goal was to apply PET technology to detect and quantify trast, no increase in binding was seen in areas of AD brain a specific pathological change in the brain. without fibrillar amyloid deposits (eg, cerebellum). Al- though neurofibrillary tangles could be stained with fluo- A␤-SPECIFIC RADIOTRACERS rescent benzothiazoles applied at a high concentration (1 µM), a 1-nM concentration of benzothiazole com- The design and biological evaluation of agents for PET pounds resulted in no increase in binding over back- and single-photon emission computed tomography to im- ground in brain tissue homogenates that contained large age A␤ plaques in the living brain have been reviewed numbers of tangles but no plaques (ie, Braak II control recently.2 The most successful radiotracers to date for these brain transentorhinal cortex). This suggested that un- purposes have proven to be relatively small molecules der in vivo PET conditions (at nM tracer levels), benzo- (Ͻ600 d), which display better in vivo pharmacokinetic thiazoles cannot detect tangle deposits and that the sig- imaging properties than large proteins such as A␤ pep- nal observed is primarily due to A␤ deposits. Finally, tides and monoclonal antibodies. Well-known A␤- multiphoton microscopy studies of PIB binding in trans- specific histological dyes, such as Congo red and thio- genic mouse models of amyloid deposition clearly dem- flavin T, have provided a starting point for the onstrated specific retention of PIB in plaque and cere- development of these agents, from which many series of brovascular amyloid deposits, confirming both brain entry analogues have been synthesized and evaluated as A␤ im- and plaque specificity in a living animal model of AD.5 aging agents for PET and single-photon emission com- puted tomography. However, the ionic charges on Congo IN VIVO PHARMACOKINETIC MODELING red and thioflavin T prevented good penetration of the blood-brain barrier by the radiotracer analogues. Neu- A primary objective of PIB PET modeling studies has been tral, lipophilic derivatives were necessary to achieve suf- to define a simple and valid method for the in vivo mea- ficient quantities of the radiotracer in the brain for sub- surement of amyloid deposition