Technology and Innovation, Vol. 18, pp. 51-61, 2016 ISSN 1949-8241 • E-ISSN 1949-825X Printed in the USA. All rights reserved. http://dx.doi.org/10.21300/18.1.2016.51 Copyright © 2016 National Academy of Inventors. www.technologyandinnovation.org

USING FOR PET IMAGING ACROSS THE ALZHEIMER’S DISEASE SPECTRUM

Ann D. Cohen

Department of Psychiatry, School of Medicine, Pittsburgh, PA, USA

Use of biomarkers in the detection of early and preclinical Alzheimer’s disease (AD) has become of central importance for the diagnosis of AD, mild cognitive impairment (MCI), and preclinical AD following publication of the NIA-Alzheimer’s Association revised criteria for diagnosis across the spectrum of AD pathogenesis. The use of in vivo PET imaging agents, such as Pittsburgh Compound-B, allows early detection of AD pathological processes and subsequent . Imaging with PiB provides early, or perhaps even preclin- ical, detection of disease and accurately distinguishes AD from of other etiologies in which the diagnostic distinction is difficult to make clinically. From a research perspective, utilizing amyloid imaging agents allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to MCI to AD. The present review focuses on use of PiB-PET across the spectrum of AD pathogenesis.

Key words: Amyloid; Alzheimer’s disease; Pittsburgh Compound B; Neuroimaging

Alzheimer’s disease (AD) is the most common aminophenyl)-6-hydroxybenzothiazole (33)), is cause of and is pathologically characterized a -T (ThT) derivative, a small molecule by the presence of containing amy- known to bind amyloid aggregated into a loid-beta (Aβ) and neurofibrillary tangles containing beta-pleated sheet structure (31). The development of hyperphosphorylated tau, as well as significant loss of amyloid imaging PET tracers, such as PiB, have made neurons and deficits in neurotransmitter systems. The the in vivo imaging of amyloid possible, with striking “amyloid cascade hypothesis” points to deposition of differences in PiB retention observed between control Aβ plaques as a central event in the pathogenesis of and AD subjects in brain areas known to contain sig- AD (16,18). This states that overproduction of Aβ, or nificant amyloid deposits in AD (e.g., frontal cortex failure to clear this peptide, leads to AD primarily and parietal cortex). through amyloid deposition, by way of the produc- Imaging AD pathology, using amyloid PET imag- tion of NFT, cell death, and, ultimately, the clinical ing agents such as PiB, has several potential clinical symptoms such as memory loss and other domains benefits, including preclinical detection of disease of cognitive impairment (17). and accurately distinguishing AD from non-AD Pittsburgh Compound-B (PiB), also known as dementia in patients with mild or atypical symp- [11C]6-OH-BTA-1 or [N-methyl-11C]2-(4’-methyl- toms or confounding comorbidities (in which the ______Accepted December 10, 2015. Ann D. Cohen, Ph.D., 1406 Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel: +1 (412) 246-6251; Fax: +1 (412) 246-6466; E-mail: [email protected]

51 52 COHEN distinction is difficult to make clinically). From a original studies provided a landmark description of research perspective, these imaging techniques allow the natural history of Aβ deposition in living sub- us to study relationships among amyloid, cognitive jects and were later confirmed by additional studies function, and neurodegenerative processes across using PiB in AD patients and cognitively normal the continuum from normal aging to AD and to subjects (4,8,10-12,24,32,34,39,43,44,52,69). A recent monitor the biological effects of anti-Aβ drugs and meta-analysis among participants with dementia relate them to effects on neurodegeneration and cog- demonstrated that amyloid positivity was associated nition. In particular, understanding biomarkers such with clinical diagnosis (i.e., AD), age, and APOE as PiB in relation to normal aging has become critical genotype. Additionally, similar associations of age given that we have entered the era of “prevention” and APOE ε4 with amyloid positivity were observed trials in AD with two studies targeting autosomal in participants with AD dementia at autopsy (41) dominant AD (DIAN and API), one study targeting (Figure 1). homozygous APOE*4 carriers (API), and one study targeting typical late-onset disease (A4). All of these AMYLOID IMAGING IN AUTOSOMAL DOMINANT studies rely heavily on biomarkers in general and on AD Aβ biomarkers in particular. A key concept underly- Roughly 1% of all AD cases are caused by single ing these trials is the NIA-Alzheimer’s Association gene mutations that are transmitted in an autoso- research criteria for preclinical AD, which argues mal dominant pattern with nearly 100% penetrance. that Aβ deposition in individuals without cognitive Familial AD has been linked to mutations in prese- impairments is, in fact, a preclinical stage of AD (55). nilin-1 (PS1, chromosome 14, the most commonly These criteria have been operationalized by Jack et involved gene), amyloid precursor (APP, al. (19) and suggest amyloid biomarkers, including chromosome 21), or presenilin-2 (PS2, chromosome PiB-PET, become abnormal first and are followed 1). All these mutations are thought to cause early-on- by biomarkers of neuronal injury and degeneration, set familial AD (eoFAD) by promoting the cleavage including FDG-PET, closer to the time when cog- of APP to the pro-aggregatory Aβ1-42 peptide (17). nitive symptoms appear (19). The present review In order to explore the natural history of preclin- focuses on use of PiB-PET across the spectrum of ical amyloid deposition in people at high risk for AD. AD, individuals with eoFAD have been evaluated in several studies. In the first PiB-PET study, subjects EARLY PiB STUDIES with two different PS1 mutations were explored (27). The earliest studies with PiB in AD patients The PS1 mutation carriers, independent of cogni- showed marked increases in PiB retention in brain tive status, showed a strikingly similar focal amyloid areas known to contain high levels of amyloid plaques deposition that appeared to begin in the striatum, in when compared to cognitively normal subjects. PiB contrast to early deposition of amyloid in non-mu- retention in AD patients was generally most promi- tation carriers, typically in the frontal cortex and nent in cortical areas and lower in white matter areas, the precuneus/posterior cingulate region but not in consistent with post-mortem studies of Aβ plaques in striatum (34). the AD brain (58). PiB retention was observed at high These data have been extended to autosomal levels in frontal cortex in AD but also was observed in dominant dementia and frequent cerebral amyloid precuneus/posterior cingulate, temporal, and parietal angiopathy and intracerebral hemorrhages due to an cortices. The occipital cortex and lateral temporal APP locus duplication (47,50). Similar to previous cortex were also significantly affected with a rela- findings, PiB retention was highest in the striatum (up tive sparing of the mesial temporal areas. Significant to 280% of the control mean), and the overall pattern striatal PiB retention also was observed, consistent of increased PiB retention was different from that with previous reports of extensive Aβ deposition seen in sporadic AD (48). Theuns et al. (59) reported in the striatum of AD patients (6,7,57,66). These widespread retention of PiB, typical of that observed USE OF PiB FOR PET IMAGING OF AD 53

Figure 1. Prevalence of Amyloid Positivity According to Age for the Different Dementia Diagnostic Groups. Reprinted from Ossenkoppele et al. (41) with permission from the American Medical Association: JAMA, copyright 2015. in sporadic AD, in a 57 y/o patient (MMSE of 18) with and cortical thinning (5) (Figure 2). Further, several a novel K724N mutation in the C-terminal intracy- groups have shown a similar striatal PiB retention tosolic fragment of APP. The subject showed no dis- pattern in older non-demented subjects with Down’s proportionate PiB retention in the striatum. However, syndrome (3,15,29,30). These early-onset forms of Villemagne et al. (62) has demonstrated increased AD all share overproduction of Ab (particularly the striatal PiB deposition in PS1 and APP mutation 42 amino acid form) as a proposed mechanism of Ab carriers. Recently, autosomal dominant Alzheimer’s deposition (68), whereas decreased clearance might disease mutation carriers have been shown to have be more important in late-onset AD (65). It may be elevated PiB levels in nearly every cortical region that the cellular milieu of the striatum is particularly 15 years before the estimated age of disease onset prone to amyloid deposition under conditions of that predates changes in cortical glucose metabolism overproduction. 54 COHEN

It has been reported that two genetic forms of AD, although other studies also found significant PiB the Arctic APP mutation and the Osaka APP muta- retention in non-amnestic MCI (67). These studies tion, were found to have little PiB retention in the have suggested that the non-amnestic MCI subtype brains of mutation carriers—in contrast to subjects may include depression or incipient dementia where with late-onset AD. Interestingly, these mutations Aβ deposition is not a feature (e.g., frontotemporal have been associated with enhanced formation of Ab or vascular dementia), or they may prove to be part oligomers without Ab fibril formation (40,60). The of the 5-10% who have stable MCI or the 20% who lack of PiB-PET signal in both the Arctic and Osaka revert to apparent normality (9,14). mutations suggests that oligomeric Ab, rather than Longitudinal studies have also suggested that MCI fibrillar bA , plays a significant role in the cause of subjects with high PiB retention are much more likely dementia symptoms observed in patients carrying to convert to AD than subjects with low PiB retention. these genetic mutations (53,54,60). Forsberg and colleagues (13) demonstrated that all seven MCI-to-AD converters were amyloid-positive AMYLOID IMAGING IN MCI at baseline, and nine of the 14 non-converters were In early studies of mild cognitive impairment amyloid-negative. In addition, none of the baseline (MCI), PiB appeared to show a bimodal distribu- PiB(-) MCI subjects converted to AD. This effect has tion, with 60%-75% of subjects showing an AD-like also been observed in several subsequent studies, with pattern of PiB retention, while the remaining subjects MCI subjects with increased PiB retention showing showed levels typical of PiB-negative [PiB(-)] controls much more frequent conversion to AD (25,28,63). (21,32,45,52). Variations in PiB retention have also Therefore, amyloid PET is likely to have a prognostic been explored when examining MCI subjects based role in the clinical evaluation of MCI by identifying on MCI subtype; subjects with non-amnestic MCI subjects who have underlying AD pathophysiology were much less likely to be PiB-positive [PiB(+)] and are therefore at high risk for further clinical than subjects with amnestic MCI (20,24,43,44,52) decline (2).

Figure 2. P value maps showing differences between carriers and noncarriers in PiB (A), FDG (B), and cortical thickness (C) at −15, −10, −5, and 0 y before predicted symptom onset. (P < 0.01 after correction for multiple comparisons) increases are shown in shades of red and decreases in shades of blue. Reprinted from Benzinger et al. (5) with permission from the National Academy of Sciences: PNAS, copyright 2013. USE OF PiB FOR PET IMAGING OF AD 55

AMYLOID IMAGING IN NORMAL COGNITION carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 Several studies have now demonstrated PiB reten- carriers, and 95 years for ε2ε3 carriers, suggesting a tion in cognitively normal controls. Depending on 20- to 30-year interval between first development of the site, reports have ranged from a proportion of amyloid positivity and onset of dementia (22). 10-30% of normal elderly subjects with significant PiB retention (i.e., PiB(+))(1,20,23,26,34-36,43,46,51,64). CONCLUSIONS PiB-PET studies have also demonstrated that ApoE4 The use of amyloid imaging, alone or in conjunc- genotype is associated with higher PiB retention in tion with other biomarkers, will likely be critical to cognitively normal elderly in a dose-dependent man- the identification of subjects at risk for AD and future ner (37,46,51), and ApoE4 carriers are more than decline, as has been suggested in the new diagnostic twice as likely to convert from PiB(-) to PiB(+) over criteria for preclinical, prodromal, and clinical AD time (46). Conversely, ApoE2 has been associated (55). One aspect of Ab pathology that has become with lower PiB retention in normal elderly (37). This clear from amyloid imaging studies is how early in the wide range likely depends on such factors as the age spectrum of AD the full burden of amyloid plaques of the cohort, proportion of subjects carrying the begins to develop. Therefore, major challenges for ApoE4 allele, definition of “cognitively normal,” and amyloid imaging will be: 1) how to determine the the threshold for defining amyloid-positivity. earliest signs of amyloid accumulation; 2) the associa- The relationship between increased PiB reten- tions of amyloid accumulation with cognitive impair- tion and cognition in the normal elderly has been ments; and, ultimately, 3) whether or not this early difficult to define, as significant plaque load is not amyloid deposition will invariably lead to clinical related to broad differences in cognitive function dementia in a high percentage of individuals. This (1,20,34,38,51). However, in other studies, an increase will likely require the field to continue to focus on in PiB retention has been associated with poorer per- cognitively normal elderly and detection of the ear- formance on episodic memory tests (23,35,36,43,64). liest signs of amyloid deposition, along with markers Additionally, a recent study of a community-based of neurodegeneration such as MRI and FDG-PET, sample demonstrated that elevated amyloid levels in order to determine the clinical significance of at baseline were associated with worse cognition pre-symptomatic pathology. Further, as anti-amy- and AD-like imaging biomarkers at baseline and loid clinical trials begin in asymptomatic individuals, with greater clinical decline and neurodegeneration. it will be critical to effectively identify the earliest Further, this study demonstrated the increased amy- changes in amyloid deposition and the significance loid was associated with clinical conversion to MCI of such changes on downstream neurodegenerative (42). In support of this finding, longitudinal studies processes. have found that cognitively normal individuals with elevated PiB are at much higher risk for longitudinal REFERENCES cognitive decline and the emergence of clinically 1. Aizenstein, H. J.; Nebes, R. D.; Saxton, J. A.; Price, significant cognitive impairment than PiB(-) age and J. C.; Mathis, C. A.; Tsopelas, N. D.; Ziolko, S. education matched subjects (37,49,56,63,64). Further, K.; James, J. A.; Snitz, B. E.; Houck, P. R.; Bi, recent theoretical models suggest that the period of W.: Cohen, A.D.; Lopresti, B.J.; DeKosky, S.T.; time from the first detection of Aβ deposition to Halligan, E.M.; Klunk, W.E. Frequent amy- levels typically seen in MCI is ~15 years, providing loid deposition without significant cognitive further evidence for an extended preclinical phase impairment among the elderly. Arch. Neurol. of AD (61). A recent meta-analysis of amyloid PET 65(11):1509-1517; 2008. imaging in non-demented individuals demonstrated 2. Albert, M. S.; DeKosky, S. T.; Dickson, D.; that the age at which 15% of cognitively normal par- Dubois, B.; Feldman, H. H.; Fox, N. C.; Gamst, ticipants were amyloid positive was approximately A.; Holtzman, D. M.; Jagust, W. J.; Petersen, R. C.; 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 Snyder, P.J.; Carrillo, M.C.; Thies, B.; Phelps, C.H. 56 COHEN

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