2014 SNMMI Highlights Lecture: Neuroscience

From the Newsline Editor: The Highlights Lecture, presented at the closing session of each SNMMI Annual Meeting, was

originated and presented for more than 33 years by Henry N. Wagner, Jr., MD. Beginning in 2010, the duties of summarizing

selected significant presentations at the meeting were divided annually among 4 distinguished nuclear and molecular medicine

subject matter experts. The 2014 Highlights Lectures were delivered on June 11 at the SNMMI Annual Meeting in St. Louis,

MO. The first presentation is included here; others will appear later this year. Nicolaas I. Bohnen, MD, PhD, spoke on

neuroscience highlights. Note that in the following presentation summary, numerals in brackets represent abstract numbers

as published in The Journal of Nuclear Medicine (2014;55[suppl 1]).

It is my distinct privilege to summarize the highlights ofthe neuroscience presentations from the SNMMI An-nual Meeting, covering the areas of basic neuroscience,

clinical neurology, and psychiatry. At this meeting, theKuhl–Lassen Award, the major award given by the BrainImaging Council, went to Osama Sabri, MD, PhD, fromLeipzig University (Germany). The Kuhl–Lassen Award isgiven annually to recognize a scientist who has made out-standing contributions and whose research in and serviceto the discipline of functional brain imaging is of thehighest caliber. Dr. Sabri has been a key researcher inEuropean studies of 18F-florbetaben, the amyloid-b (Ab)ligand that received recent approval from the U.S. Foodand Drug Administration (FDA). He is also in the fore-front of research in PET/MR imaging of the brain and inthe development of a new ligand, 18F-flubatine, to studya4b2-nicotinic acetylcholine receptors (a4b2-nAChRs) inAlzheimer disease (AD).

It is also my privilege to recognize the young and verytalented scientists honored at the Brain Imaging YoungInvestigators Awards session at this meeting. The winnerwas Dustin Wooten, PhD, who, with colleagues at HarvardMedical School and Massachusetts General Hospital(Boston) and the Massachusetts Institute of Technology(Cambridge), reported on “Occupancy and functional re-sponse to D1 receptor ligands assessed by concurrent PET/fMRI” [30]. The second place award went to MatthiasBrendel, PhD, who, with colleagues at the University ofMunich (Germany), Tohoku University (Sendai, Japan),and the German Center for Neurodegenerative Diseases(Munich), reported on “PET imaging of tau pathology ina transgenic mouse model using [18F]THK-5117” [28]. Thethird-place award went to Phillip Hsu, who, with colleaguesfrom Washington University (St. Louis, MO), reported that“Longitudinal amyloid deposition is associated with changesin cortical thickness and white matter integrity in cognitivelynormal adults” [33].

Dementia and Neurodegenerative Disease

A major focus for neuroscience for the last several yearshas been on dementia and neurodegenerative conditions,and this continues to be true. We now have 3 Ab PETligands approved by the FDA: 18F-florbetapir, 18F-fluteme-tamol, and 18F-florbetaben. One of the largest studiescorrelating PET findings with postmortem analyses (a cor-relation required by the FDA for approval) was presented

at this meeting by Seibyl et al.on behalf of the FlorbetabenStudy Group, including authorsfrom the United States, Germany,Japan, and Australia. In “A nega-tive florbetaben PET scan reliablyexcludes amyloid pathology asconfirmed by histopathology”[243], these authors reported on74 patients imaged with 18F-flor-betaben PET shortly before theend of life (Fig. 1), followed bypostmortem examination. Scansfrom 46 of the 47 patients deter-mined at postmortem to be Ab-positive were also correctlyread on PET as positive; scans from 24 of the 27 subjectswithout Abwere correctly read as negative; 24 of 25 scansread as negative were correctly assessed. Sensitivity, spec-ificity, and negative predictive values were 98%, 89%, and96%, respectively, making it a very useful ligand for clin-ical practice. The presence of other neuropathologies didnot influence the assessment of scans in this study.

As we know, Ab deposition in AD does not happenovernight. It is a slowly evolving process that we now be-lieve extends 15 or more years before conventional symp-tomatic presentation. This has led to the development ofnew clinical diagnostic criteria for AD, in which Alzheimerdementia is only the end-stage of a slowly evolving disease.The challenge is to focus on the clinically silent and pro-dromal stages of AD, when patients are developing Abplaques in the brain but remain cognitively normal. TheNational Institute on Aging and the Alzheimer’s Associationhave proposed new presymptomatic diagnostic criteria as a first

step in this focus,with stage 1 la-beled “asymptom-atic amyloidosis,”stage 2 as “amy-loidosis plus neuro-degeneration,” andstage 3 as “amy-loidosis plus neu-rodegenerationplus subtle cogni-tive decline,” fol-

Nicolaas I. Bohnen,MD, PhD

FIGURE 1. 18F-florbetaben PET imagesnegative (left) and positive (right) for Aβcorrelated closely with postmortem pathol-ogy findings.

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lowed by mild cog-nitive impairment(MCI) and thenAlzheimer demen-tia. PET is an es-sential element inproviding evidenceto differentiateamong these pre-symptomatic stages.Vlassenko et al.from WashingtonUniversity (St. Louis,

MO) reported on the “Relationship between brain Ab de-position and cerebrospinal fluid (CSF) Ab42 several yearsprior to amyloid positivity” [188]. They studied patientsbetween the ages of 50 and 70 years who had initially neg-ative 11C-Pittsburgh compound B (11C-PiB) Ab scans andfollowed these patients closely for several years. When

looking at those whoconverted from a negativeto positive Ab scan duringthe follow-up period, theresearchers found intrigu-ing results. CSF changesfor Ab42 were alreadyevident at the time of theoriginal negative scan inindividuals who wouldconvert 2 or 3 years laterto a positive Ab scan.They concluded that reduc-tions in CSF Ab42 are cou-pled with Ab depositionthroughout the process ofAb accumulation and thatthis process appears to beginyears before reaching theglobal brain threshold forAb positivity. This high-lights the fact that in thisclinically silent phase of thedisease, much is happeningin the brain—and we nowhave tools to more fully in-vestigate this activity.

Ab accumulation is,of course, only half ofthe pathology needed tomake a postmortem diag-nosis of AD. The otherpathology is tau neurofi-brillary tangle deposition.At this meeting we heardreports on promising newtracers with which to

study these tangles in the living brain. Okamura et al. fromTohoku University Hospital and School of Medicine (Sen-dai, Japan) reported on “In vivo selective imaging of taupathology in AD with 18F-THK5117” [136]. This novelPET tracer selectively labels neurofibrillary tangles in theAD brain. AD patients showed retention of the tracer morein the medial than lateral temporal cortices (Fig. 2), areasknown to contain high concentrations of tau deposits. 18F-THK5117 retention was correlated with the severity of de-mentia and brain atrophy in these patients. These findingssuggest that 18F-THK5117 PET would be useful for non-invasive evaluation of tau pathology in AD patients andcould perhaps lead to a better understanding of the patho-physiology of AD.

Suhara et al. from the National Institute of RadiologicalSciences (Chiba-shi, Japan) reported on “In vivo tau PETimaging using [11C]PBB3 in AD and non-AD tauopathies”[1824]. These authors very nicely showed that we can usethis ligand to track patients from MCI through severe de-mentia. Figure 3 shows that the intensity of tracer uptakecorrelated well with disease progression in terms of cogni-tive impairment. The authors also noted that 11C-PBB3binding has the potential to increase our understanding oftau protein–related neurologic manifestations in cortico-basal syndrome, progressive supranuclear palsy, and fron-totemporal dementia.

New Technologies and Ligands

Another major new field highlighted in many sessions atthis meeting was that of PET/MR imaging in brain studies.Bohn et al. from the Technische Universitat Munchen (Ger-many) reported on “Simultaneous 18F-FDG PET, pulsedarterial spin labeling (PASL) MRI and structural MRI inneurodegenerative dementia: a PET/MR study” [411]. Theyshowed converging and overlapping patterns affecting bothglucose metabolism and changes in blood flow (Fig. 4).They also showed that PASL MR imaging delivers resultscomparable to those with 18F-FDG PET in patients withneurodegenerative AD. This highlights a proof of conceptthat with PET/MR imaging we may develop “one-stopshopping” for dementia diagnosis, with the ability to simul-taneously assess function and anatomy.

We are always hoping for a cure for neurodegenerativediseases such as Parkinson disease and amyotrophic lateralsclerosis (ALS). To better study promising stem cell applica-tions in these diseases we need markers that can monitor thefate of these cells once grafted in the brain. Lewis et al. fromthe University of Wisconsin (Madison) reported on “DMT1,a novel PET/MR reporter protein for neural stem cell track-ing” [60]. These authors showed transfection of human stemcells with a divalent metal transporter that has both a manga-nese MR agent as well as 52Mn, a PET ligand. The animalimages in Figure 5 show the results of simultaneous in vivoimaging with the PET marker and the MR agent. This tech-nique holds promise for dual-modality cell tracking in thecentral nervous system (CNS).

FIGURE 2. Tau and Aβ pathologies inAD visualized by, respectively, 18F-THK5117 (left) and 11C-PiB PET (right).18F-THK5117 retention was correlated withseverity of dementia and brain atrophy inAD patients.

FIGURE 3. 11C-PBB3 bindingin AD and non-AD tauopathies.Uptake in: (top) healthy elderlyindividual; (middle) individual withAD-related MCI; (bottom) indi-vidual with AD. The spectrum of11C-PBB3 binding correlates withseverity of clinical symptoms inindividuals with AD and AD-related MCI.

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Nabulsi et al. from Yale University (New Haven, CT)and UCB Pharma SA (Brussels, Belgium) reported on “11C-UCB-J: a novel PET tracer for imaging synaptic vesicleglycoprotein 2A (SV2A)” [355]. This is a much-neededtracer in the field of epilepsy for imaging and quantifyingsynaptic vesicle glycoprotein 2A activity. These researchersreported on initial analyses and dosimetry. Figure 6 showsexcellent uptake in studies in rhesus monkeys, as well asvery specific blocking of the ligand by the anti-epilepticagent levetiracetam. The authors concluded that 11C-UCB-J is suitable for PET imaging of SV2A in nonhuman pri-mate brains and reported that human studies are underway.

For many years in neuroscience we have focused onwhat is called the “first messenger” system: the binding of

a neurotransmitter to a receptor. Much more is happeningwithin the cell, and these processes are referred to as the“second messenger” system. It is quite intriguing to see thatwe now have ligands that bind intracellularly to the elementsand enzymes of the second messenger system. For example,Niccolini et al. from the Imperial College London, King’sCollege London, the UCL Institute for Neurology, andImanova (all in London, UK) reported on “Brain phospho-diesterase 10A (PDE-10A) density in early premanifestHuntington’s disease (HD) gene carriers” [32]. The authorsused 11C-IMA-107 PET imaging to study a unique cohortof early premanifest HD gene carriers to investigate theexpression of PDE-10A (one of the enzymes needed inthe conversion of cyclic adenosine monophosphate [cAMP]to AMP). They quantified the availability of PDE-10A inthe brains of 12 early premanifest HD gene carriers witha mean of 25 years (range, 17–43 years) before the pre-

FIGURE 4. Coregistered color-coded statistical parametric mapping images (multicolored images) and pulsed arterial spin–labeled(PASL) MR images (blue and gray images) acquired in patients with (left 2 image blocks) AD and (right 2 image blocks) MCI. T1-weighted magnetization–prepared rapid acquisition gradient echo MR (yellow); PASL MR (blue); 18F-FDG PET (red).

FIGURE 5. Studies with 52Mn-DMT1, a novel PET/MR agent,tracking transfected human stem cells in mice. Top: Ex vivo PET(left) showed tracer uptake in transfected cells, confirmed byautoradiography (right). Bottom: In vivo (left) and in vitro (right)MR imaging showed increased T1 relaxation rate in areas ofuptake of a manganese MR agent.

FIGURE 6. 11C-UCB-J PET imaging of synaptic vesicle glyco-protein 2A (upper row). Blocking with 10 mg/kg levetiracetamyielded ∼65% receptor occupancy in nonhuman primate brain(bottom row).

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dicted onset of clinical symptoms and in 12 matchedhealthy controls. They found that although early premani-fest HD gene carriers were clinically normal, 11C-IMA-107 PET revealed bidirectional changes in PDE-10A ex-pression, with 17%–33% decreases in striatum, 26% decreasesin globus pallidus, and 35% increases in motor thalamic nu-clei compared to the healthy controls (Fig. 7). This opensup a new area of promise for treatment in the prodromalphase in this disorder.

We also have new ligands with which to study oxidativestress based on mitochondrial dysfunction. ALS, for example,is a debilitating motor neuron disease with poor clinical outlookand for which novel radioligands are needed for insight

into disease pathogenesisand progression. Okazawaet al. from the Universityof Fukui and Fukui Prefec-tural University (both inEiheiji-cho, Japan) reportedon “Evaluation of cerebraloxidative stress in ALSusing 62Cu-ATSM PET”[1831]. Analyses showedsignificantly greater accu-mulation of this tracer in bi-lateral motor cortices and inthe right parietal cortices ofALS patients than inhealthy controls (Fig. 8).Standardized uptake valuesin bilateral motor corticesof ALS patients were alsosignificantly higher. Theresults were inversely corre-lated with clinical ratings ofseverity of disease in ALSpatients.

Barret et al. from Molecular Neu-roImaging LLC (New Haven, CT) andUCB Pharma SA (Brussels, Belgium)reported on “In vivo assessment of[18F]MNI-444 in human brain: a noveladenosine 2A (A2A) receptor PETtracer” [356]. The A2A receptor, asa binding substrate for caffeine, alsohas significant clinical implicationsfor disorders such as Parkinson dis-ease. These researchers provided thefirst full validation in humans ofthis 18F-labeled PET tracer for A2A,allowing noninvasive analysis over90 minutes using the cerebellum asa reference region” (Fig. 9).

Brain Tumors

Participants in the SNMMI AnnualMeeting presented a number of interesting ligands withwhich to target the pathology of tumors, as well as newinformation on the many radioisotopes that can be used tolabel these agents. For example, Wehrenberg-Klee et al.from Massachusetts General Hospital (Boston) reported on“A F(ab)’2-based epidermal growth factor receptor(EGFR)–targeted PET probe for glioma imaging” [1793].64Cu-DOTA-cetuximab-F(ab’)2 binds to EGFR, which isexpressed on the surface of 40%–60% of glioblastoma mul-tiforme cells. The animal model images in Figure 10 showa very high initial tumor-to-background tissue ratio, withsignificant reduction after cetuximab administration.Images after partial and complete resection show the spec-ificity of the probe for tumor persistence after surgery.

A ligand for angiogenesis studies was presented byIagaru et al. from Stanford Hospital and Clinics (CA), whoreported on “18F-FPPRGD2 PET/CT evaluation of patients

FIGURE 7. 11C-IMA-107 binding in the striatum in healthy controls (top row) wasgreatly decreased in early premanifest Huntington disease gene carriers (bottom row).

FIGURE 8. 62Cu-ATSM PETand cerebral oxidative stress inALS. Statistical parametric map-ping image analysis, with medialmotor cortices showing signif-icantly higher accumulation oftracer in patients with ALS.

FIGURE 9. 18F-MNI-444 PET as an adenosine 2A receptor tracer:MR (top row), PET, (middle row), fused MR/PET (bottom row).

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with suspected recurrence of glioblastoma multiforme” [31]after treatment with bevacizumab. These authors showedthat response could be predicted in as little as 1 week aftertreatment. On the left in Figure 11 are images from a par-ticipant who showed only a 4.8% reduction in uptake at 1week; on the right is a patient who showed a 59.8% re-duction at 1 week. The first patient died 4 months aftertreatment; the second was stable at 27 months.

Hall et al. from the University of Wisconsin andNovelos Therapeutics (both in Madison, WI) reported on“Comparison of MRI and 124I-CLR1404 PET/CT in pri-mary and metastatic brain tumors” [525]. This radiola-beled phospholipid ether analog enters malignant cells

via membrane lipid rafts and is over-expressed in malignant cells. In morethan 50 preclinical models, includinggliomas, the researchers found tu-mor-specific uptake and prolongedretention of this tracer. The tracer isalso suitable for isoteric iodine sub-stitution, with 124I for molecular/PET imaging and 131I for therapy.Related optical imaging agents arealso being developed. Figure 12shows that the tracer not only picksup the primary CNS gliomas but alsoCNS metastases from non–small celllung cancer.

Psychiatry

Although the number of submis-sions in this category was relatively lowat this meeting, their high quality wasimpressive. Meyer et al. from the

University of Leipzig (Germany) reported on “a4b2-nAChRbinding in acute unmedicated major depressive disorder(MDD): a 2-[18F]F-A-85380 PET study“ [83]. These research-ers found significantly lower corticolimbic and paralimbica4b2-nAChR availability in acute unmedicated MDDpatients than in healthy controls, and these decreases weredirectly correlated with severity of disease (Fig. 13). Suchresults provide new windows on potential treatments fordepression.

FIGURE 10. 64Cu-DOTA-cetuximab-F(ab’)2 PET glioma imaging in a mouse model. (A)Very high tumor-to-background ratio (left column) and significant reduction in uptakeafter cetuximab administration (right column). (B) Bioluminescence imaging, PET/CT,and sagittal PET/CT (left to right) at complete (top row) and partial (bottom row)resection showed the specificity of the probe.

FIGURE 11. 18F-FPPRGD2 PET/CT in 2 patients with sus-pected recurrence of glioblastoma multiforme after treatment withbevacizumab. Images show (top to bottom) MR, 18F-FPPRGD2PET, and fused PET/MR images before (left) and after (right) initi-ation of treatment. The patient in the left block of images showedonly a 4.8% reduction in uptake at 1 week and died 4 monthslater. The patient in the right block of images showed a 59.8%reduction at 1 week and was stable at 27 months.

FIGURE 12. 124I-CLR1404 (also called NM404) PET studies.Top row: patient with non–small cell lung cancer. Left to right:18F-FDG PET, 124I-CLR1404 PET, and contrast MR imagingshowing striking image contrast differences between low 18F-FDG and very intense phospholipid ether analogue uptake inright temporal metastasis. Bottom row: patient with WorldHealth Organization stage III glioma. Left 2 images: T2-weighted and contrast-enhanced MR images show wide areaof edema but more limited area of abnormal MR contrast en-hancement in left parieto-occipital glioma. Right 2 images:phospholipid ether analogue PET shows intense tracer uptake,and fused PET–contrast MR image shows larger area of abnor-mal PET tracer uptake than MR contrast enhancement in thetumor.

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The imagingof the second mes-senger system asa novel way tounderstand braindisease was men-tioned earlier inthe context ofHD. Another ex-ample was pre-sented by Fujitaet al. from the Na-tional Institute ofMental Health(Bethesda, MD)and Johnson &Johnson (NewBrunswick, NJ),who reported on“Cyclic AMP cas-cade in MDD im-

aged with 11C-(R)-rolipram: downregulation in unmedicatedpatients and normalization by antidepressant treatment” [81].In unmedicated MDD patients, tracer uptake was severelyreduced in comparison with uptake in healthy controls (Fig.14). However, the use of antidepressants normalized uptakein MDD patients, with increases in 11C-(R)-rolipram bindingcorrelating with symptom improvement. This PET study of

a second messenger system in MDD confirms the cAMPtheory of depression and of antidepressant action and sug-gests that MDD can be treated with PDE-4 inhibitors.

Hesse et al. from the University of Leipzig (Germany) incollaboration with the New York University School of Medicine(NY) reported that “Stress response and impulsivity are relatedto noradrenaline transporter availability in obesity” [86]. Theresearchers used 11C-MRB, a norepinephrine transporter ligand,to investigate whether central noradrenaline transporter availabil-ity is altered in relation to stress response in extremely obeseindividuals as a pathomechanism in obesity (Fig. 15). They usedthe dexamethasone suppression test to determine stress hormoneresponsiveness in obese individuals. Their data suggest a patho-mechanism of a higher noradrenergic tone (higher arousal) inobesity, which is related to an altered stress response and im-pulsive behavior. This provides new insights on why obeseindividuals may maintain obesity despite interventions.

Conclusion

The neuroscience presentations at this meeting were quiteintriguing and introduced many new leads for diagnosis andmonitoring of treatments, as well as leads for developmentof new treatments for patients with CNS disorders.

Nicolaas I. Bohnen, MD, PhDUniversity of Michigan Medical School and

Veterans Affairs Medical CenterAnn Arbor, MI

FIGURE 13. 2-[18F]F-A-85380 PET inpatients with acute unmedicated majordepressive disorder (MDD). Statisticalparametric images show areas of de-creased α4β2 nicotinic receptor binding(depicted in yellow) in corticolimbic (orbi-tofrontal), limbic regions, and the poste-rior cingulum in patients with MDDcompared to control subjects.

FIGURE 14. 11C-(R)-rolipram PETimages in healthy controls (left) and un-medicated patients with major depres-sive disorder (MDD, right). Severedecreases in binding were seen inMDD patients, but these decreasesnormalized after ∼8 weeks of selectiveserotonin reuptake inhibitor therapy.

FIGURE 15. 11C-MRB PET and stress response in obesity. Selected MR, 11C-MRBPET, and fused PET-MR transaxial image slices centered at subcortical gray structures(basal ganglia, thalami; first 3 images from left) and brainstem at the level of the locusceruleus (3 images from right), showing regional cerebral noradrenaline transporteravailability. Correlational analysis between regional cerebral PET noradrenaline trans-porter availability, stress hormone responsiveness, and behavioral ratings of impul-siveness showed evidence of higher noradrenergic tone (higher arousal) in obeseindividuals, factors related to an altered stress response and impulsive behavior.

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2014;55:9N-14N.J Nucl Med.     2014 SNMMI Highlights Lecture: Neuroscience

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