Neurology International 2018; volume 10:7666

PET imaging of 18F- preservation of the GABAergic neuron pop- in cognitively impaired individ- ulation within dysfunctional posterior pari- Correspondence: Michael A. Meyer, etal cortical regions of Alzheimer disease Department of Neurology, Guthrie Clinic, 130 uals: Lack of activity within the patients.1,2 Centerway, Corning, NY 14830, USA. cerebellar cortex Much interest has been generated on the Tel.: +1.607.973.8000. use of 18F and 11C labeled compounds that E-mail: [email protected] Michael A. Meyer, Allison Caccia, bind to amyloid plaque on postmortem brain tissue sections, but generate conflict- Key words: PET; florbetapir; amyloid; cere- Danielle Martinez, Mark A. Mingos bellum; Alzheimer’s disease. ing data with regards to their in-vivo distri- Departments of Neurology and Nuclear bution after intravenous injection to living Funding: we acknowledge the contributions of Medicine, Guthrie Clinic, Sayre PA, subjects. Detailed neuropathologic studies the IDEAS Study and its collaborators USA over many years have consistently shown (www.ideas-study.org) amyloid deposition within cortical regions in a non-homogenous distribution with pre- Acknowledgements: The authors wish to dominance of involvement within the tem- thank Jon-Kar Zubieta, MD, PhD Abstract poral lobes; however the new PET agents Stimson Presidential Endowed Chair of that display amyloid binding in-vitro dis- Psychiatry, University of Utah for reviewing Ten individuals suspected of having play surprisingly high levels of activity the manuscript. possible Alzheimer disease underwent PET throughout the white matter in a confluent imaging using 18F-Flubetapir. Only one of somewhat symmetric manner in vivo - for Received for publication: 2 March 2018 Accepted for publication: 18 June 2018. ten individuals had a pattern typical for nor- those affected with AD, there is additional mal elderly control subjects with 9 of the 10 penetration of tracer into the cerebral cortex This work is licensed under a Creative showing a Alzheimer type pattern for the and does not display the anticipated region- Commons Attribution NonCommercial 4.0 cerebral cortex yet all 10 subjects had uni- al differences (no obvious proclivity for the License (CC BY-NC 4.0). formly low to absent tracer localization to hippocampus and temporal lobe structures). the cerebellar cortex; significantly high Furthermore, cerebral retention of the 18F- ©Copyright M.A. Meyer et al., 2018 tracer activity was noted within the subcor- flubetapir tracer is not convincingly demon- Licensee PAGEPress, Italy tical white matter of the cerebellum in a strated on time activity curves after IV Neurology International 2018; 10:7666 doi:10.4081/ni.2018.7666 symmetric manner in all cases. In consider- injection with patterns showing a spike after ation of studies that have shown amyloid injection with subsequent wash out from deposits within the cerebellar cortex in 90% cerebral tissues.3,4 As there is rapid metabo- of pathologically proven cases of lism of the tracer with only 35% of described here ranged from 68 to 85 years Alzheimer’s disease, these findings raise unchanged parent remaining at 10 minutes,3 (mean age: 75.5 years); disease severity questions about the actual clinical value of it was suspected that tracer localization of ranged form mild to moderate to severe for florbetapir PET imaging in evaluating cere- the brain may depend on other factors such suspected Alzheimer’s disease. No adverse bellar involvement and raises questions as Alzheimer related alterations in blood events were observed; all patients were re- whether PET imaging of this tracer accu- brain barrier permeability to the labeled evaluated at the 90-day mark after PET. rately portrays patterns of amyloid deposi- metabolites. Since amyloid plaques are well Reconstructed images in the sagittal and tion, as there is rapid hepatic metabolism of described in the cerebellum of Alzheimer coronal planes through the cerebellum were the parent compound after intravenous patients,5 further investigation was carried selected for composite review and compari- injection. Possible links to Alzheimer’s dis- out here to understand why there is essen- son. ease related alterations in blood-brain barri- tially absent flubetapir tracer activity within er permeability to the parent compound and the cerebellar cortex. subsequent radiolabelled metabolites are discussed as potential mechanisms that Results could explain the associated localization of the tracer to the brainstem and subcortical Materials and Methods As shown in figure one, adequate qual- white matter within the cerebrum and cere- ity PET images were obtained in all ten bellum of Alzheimer’s disease patients. Participants for the IDEAS trial signed cases without significant motion artifact. informed consent forms approved by the Only one of ten cases had lack of penetra- institutional review board. Imaging of intra- tion of tracer into the cerebral cortex, con- venously administered 18F-flubetapir (5 to sistent with a pattern thought to be inconsis- Introduction 10 mCi) was accomplished per the standard tent with Alzheimer’s disease. This 70 year protocol followed of the IDEAS trial with old patient (case number 10; Figures 1 and Alzheimer’s disease is a devastating PET imaging commencing 30 minutes after 2A) had unusual encephalopathic behavior health problem of an increasing magnitude injection and lasting 15 minutes with CT and squinting of her eyes with memory loss within the expanding aging population that attenuation correction applied. All partici- that later improved with resolution of ocular requires definitive diagnostic methods. In pants had vitamin B12 and TSH measured abnormalities. A typical Alzheimer case is this regard, 18F-FDG PET imaging has prior to entry, and all had brain CT or MRI shown in Figure 1 (case 1) and Figure 2B been proven to be very helpful in identify- within 12 months of the study. Although not revealing diffuse penetration of tracer into ing areas of focal posterior parietal required by the IDEAS trial, all patients the cortical regions; the patient is a 78 year hypometabolism linked to Alzheimer’s dis- described here had brain SPECT or PET old with moderately severe memory loss ease (AD); other PET imaging methods imaging of the brain as well of cerebral per- attributable to late onset Alzheimer’s dis- include 11C- that reveals no loss fusion or metabolism respectively. ease with a left posterior parietal perfusion of benzodiazepine receptors and hence Ages for the study group of 10 participants defect noted on SPECT. However, in both

[page 90] [Neurology International 2018; 10:7666] Article of these two cases, as well for all the other the ability to cross the cortical blood-brain The lack of tracer activity in the cere- 8 cases, there was little to no tracer activity barrier of Alzheimer patients but not in nor- bellum is of concern as multiple pathologic evident in the cerebellar cortex (Figure 1). mal individuals as one possible yet studies confirm the presence of amyloid Although the subcortical white matter dis- unproven explanation of the imaging data. plaques in Alzheimer disease. Braak and played significant activity within the sub- cortical white matter of both cerebellar hemispheres, little to no activity was found in the cerebellar cortex. Surprisingly intense activity was consistently seen within the brain stem (see cases 5,7,9,10 with case 9 showing more intense activity in the brain stem and cerebellar subcortical white matter than the occipital and parietal cerebral cor- tex), which is seemingly inconsistent with the known patterns of amyloid deposition in Alzheimer’s disease. As prior pathologic studies have shown a gradient of A4 beta amyloid activity in AD, where more plaques were seen in the midbrain and least in the medulla,6,7 with healthy controls showing little to no brain stem plaque, the PET scan findings become hard to explain; as explained below, it is hypothesized that 18F-flubetapir metabolites with no specific avidity for amyloid could contribute signif- icantly to the image and appear in the brain stem, related to possible alterations in the blood-brain barrier but this is only hypo- thetical and not proven in any way.

Figure 1. Composite analysis of all ten patients displaying 18F-flubetapir in the sagittal Discussion and coronal planes. Although the parent compound has been shown to bind to amyloid plaques within postmortem tissue, its’ distribution in-vivo after intravenous injection is likely variable due to rapid metabolism with pos- sible variable permeability of the labeled metabolites in being able to cross the blood- brain barrier. However, recent studies have shown that the parent compound is rapidly metabolized with only 35% of unchanged parent remaining at 10 minutes.3 Dynamic whole body imaging at sequential time points after injection document rapid hepat- ic metabolism, with very little activity left in the brain by 30 minutes later with fairly intense activity passing from the into the gallbladder at that time point;6 highest radiation absorbed dose were the gallblad- der, upper large intestine, small intestine, liver, and urinary bladder at 143, 75, 66, 64, and 27 μSv/MBq, respectively. Appreciable minor bladder activity becomes evident by 186 minutes post injection. Time activity curves demonstrate an initial spike followed by rapid wash out from the cerebellar and cerebral cortex;4 there appears to be no pat- tern for extraction and retention by the brain with no pattern for increasing activity over time - only steady washout is noted, much Figure 2. PET images depicting negative results (top) and positive results consistent with of which likely consists of radiolabelled Alzheimer’s disease (bottom). hepatic metabolites that may possibly have

[Neurology International 2018; 10:7666] [page 91] Article colleagues found large numbers of amyloid positive when started after 75 Function. J Nucl Med 2017;58:1483-9. plaques in the cerebellar cortex of demented years. They also studied brain stem involve- 4. Wong DF, Rosenberg PB, Zhou Y, et al. individuals but not in controls. Most of the ment and noted that the severity of cerebel- In vivo imaging of amyloid deposition plaques were seen in the molecular layer8 lar changes corresponded to the involve- in Alzheimer disease using the radioli- and were large and extended from the upper ment of the brain stem nuclei that are gand 18F-AV-45 (florbetapir [correct- surface down to the Purkinje cell layer. known to interconnect with the cerebellar ed] F 18). J Nucl Med 2010;51:913-20. Yamaguchi et al. described beta amyloid cortex. 5. Mann DM, Jones D, Prinja D, Purkiss plaques in the molecular layer of the cere- MS. The prevalence of amyloid (A4) 9 bellum. Mann et al. studied the cerebellum protein deposits within the cerebral and of Down’s syndrome cases and concluded cerebellar cortex in Down’s syndrome that: …diffuse plaques of the cerebellum Conclusions and Alzheimer’s disease. Acta and striatum contain only A beta 42(43) and In summary, it is clear that the cerebel- Neuropathol 1990;80:318-2. that, in contrast to those of the cerebral cor- lum is significantly affected in Alzheimer’s 6. Joshi AD, Pontecorvo MJ, Adler L, et tex, these do not ‘mature’ during their life- disease. A 12.7% reduction in cerebellar al. Radiation dosimetry of florbetapir F time into A beta 40 containing plaques.10 volume has been noted15 in severely affect- 18. EJNMMI Res 2014;4:4. Barcikowska et al. studied brain tissue from ed Alzheimer disease patients analyzed 7. Brilliant M, Elble RJ, Ghobrial M, 100 stroke patients older than 80 years, of postmortem. For reasons that are not yet Struble RG. Distribution of amyloid in whom 18% had dementia and found posi- clear, in-vivo study of 18F-Flubetapir by the brainstem of patients with tive amyloid immunoreactivity in the cere- PET fails to reveal any significant activity brum in 71 of 100 cases; cerebella of 31 Alzheimer disease. Neurosci Lett within the cerebellar cortex of Alzheimer subjects of 71 with cerebral amyloidosis 1992;148:23-6. disease patients studied here, raising ques- also revealed amyloid deposits.11 8. Braak H, Braak E, Bohl J, Lang W. tions regarding the specificity of the tracer. Wegiel and colleagues12 carefully stud- Alzheimer’s disease: amyloid plaques Rapid hepatic metabolism of the tracer has ied cerebellar morphometrics and amyloid in the cerebellum. J Neurol Sci been discussed here, raising questions plaque morphology in severe final stages of 1989;93:277-87. regarding the likelihood that radiolabelled Alzheimer’s and concluded that significant 9. Yamaguchi H, Hirai S, Morimatsu M, et metabolites with no specific ability to bind atrophy was found with a decrease in the al. Diffuse type of senile plaques in the amyloid may heavily contribute to the volume of the molecular layer by 24% and cerebellum of Alzheimer-type dementia activity imaged at the 30 to 45 minute time a decrease of the granular layer by 22% in demonstrated by beta protein immunos- interval after injection; the possibility of comparison with controls. The 32% tain. Acta Neuropathol 1989;77:314-9. altered blood-brain barrier permeability to decrease in the total number of Purkinje 10 Mann DM, Iwatsubo T. Diffuse plaques the parent compound and subsequent neurons were found along with a 30% in the cerebellum and corpus striatum in metabolites need to be considered here as reduction in the number of granule cells. Down’s syndrome contain well. Overall, it is concluded that 18F-flor- They concluded that the …correlation protein (A beta) only in the form of A betapir PET imaging was insensitive to between the temporal duration of AD and detecting cerebellar amyloid deposits in this beta 42(43). Neurodegeneration both the decrease of the total number of relatively small study of 10 patients; this 1996;5:115-20. granule cells (r=0.86, P<0.01) and the vol- stands in contrast to the fact that significant- 11. Barcikowska M, Kujawa M, umetric loss of the molecular (r=0.73, ly numerous cerebellar amyloid plaques Wiśniewski H. beta-Amyloid deposits P<0.05) and granular (r=0.93, P<0.001) have been found by numerous postmortem within the cerebellum of persons older layers of the cerebellar cortex indicates that neuropathologic studies. More research is than 80 years of age. Neuropatol Pol these cerebellar atrophic changes are likely clearly needed. 1992;30:285-93. to be related to the basic pathologic process 12. Wegiel J, Wisniewski HM, of AD. Similarly, the correlation between Dziewiatkowski J, et al. Cerebellar atro- the most complex parameter the atrophy of phy in Alzheimer’s disease-clinico- the cerebellar cortex and the Functional References pathological correlations. Brain Res Assessment Staging (FAST) measure of the 1999;818:41-50. clinical severity of AD at the time of demise 1. Mann DM, Jones D, Prinja D, Purkiss 13. Joachim CL, Morris JH, Selkoe DJ. (r=0.63, P<0.05) as well as with the dura- MS. The prevalence of amyloid (A4) Diffuse senile plaques occur commonly tion of AD (r=0.78, P<0.01) indicates that protein deposits within the cerebral and in the cerebellum in Alzheimer’s dis- cerebellar , when viewed holisti- cerebellar cortex in Down’s syndrome cally, evolves continuously in association and Alzheimer’s disease. Acta ease. Am J Pathol 1989;135:309-19. with clinical changes throughout the clini- Neuropathol 1990;80:318-27. 14. Cole G, Neal JW, Singhrao SK, et al. cally manifest course of AD. 2. Meyer M, Koeppe RA, Frey KA, et al. The distribution of amyloid plaques in Selkoe and colleagues found that dif- Positron emission tomography meas- the cerebellum and brain stem in fuse cerebellar plaques were detected in 47 ures of benzodiazepine binding in Down’s syndrome and Alzheimer’s dis- of 100 cases of clinically and pathologically Alzheimer’s disease. Arch Neurol ease: a light microscopical analysis. diagnosed AD and in none of 40 control 1995;52:314-7. Acta Neuropathol 1993;85:542-52. subjects.13 The 1993 study of Cole and col- 3. Ottoy J, Verhaeghe J, Niemantsverdriet 15. Andersen K, Andersen BB, Pakkenberg leagues14 revealed an important age effect: E, et al. Validation of the B. Stereological quantification of the cerebellar amyloid plaques were found in Semiquantitative Static SUVR Method cerebellum in patients with Alzheimer’s 93% in those who developed dementia for 18F-AV45 PET by Pharmacokinetic disease. Neurobiol Aging before 65 years of age; only 56% cases were Modeling with an Arterial Input 2012;33:197.e11-20.

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