inNeurology ComputedTomography Single-PhotonEmission ... · PositronEmission Tomographyand Single-PhotonEmission ComputedTomography inNeurology RobertS.Miletich,MD,PhD,FAAAS ABSTRACT

Positron EmissionTomography andSingle-Photon EmissionComputed Tomographyin Neurology

Robert S. Miletich, MD, PhD, FAAAS

ABSTRACTPurpose of Review: Positron emission tomography (PET) and single-photon emissioncomputed tomography (SPECT) are now available for routine clinical applications inneurology. This article discusses their diagnostic use in dementia, brain tumors, epilepsy,parkinsonism, cerebrovascular disease, and traumatic brain injury.Recent Findings: Neuromolecular imaging, also known as nuclear neurology, involvesclinical imaging of both basal regional physiology (perfusion, metabolism, and transportmechanisms) and specific neurochemical physiology (currently, only the dopaminetransporter). This article serves as an introduction to neuromolecular imaging, review-ing the literature supplemented by the author’s experience.Summary: Neurologic PET and SPECT are no longer restricted to the research realm.These modalities have high diagnostic accuracy.

Continuum (Minneap Minn) 2016;22(5):1636–1654.

INTRODUCTIONThis article discusses the clinical ap-plication of neuromolecular imaging,also known as nuclear neurology,focusing on tomographic methodsthat are currently available and acces-sible in routine clinical care, if regionalexpertise exists. Planar scintigraphymethods, in which a two-dimensionalimage is created of a three-dimensionalobject, such as in nuclear cisterno-graphy or spine bone scans, are notreviewed in this article. The focus ison literature from the past 5 yearssupplemented by the author’s clinicalexperience. Clinical neuromolecularimaging examines the central nervoussystem distribution of US Food andDrug Administration (FDA)Yapproved

radiopharmaceuticals for positronemission tomography (PET) andsingle-photon emission computed to-mography (SPECT). In the author’sexperience, medical insurance usuallyreimburses for both the radiopharma-ceuticals and the imaging tests reviewedin this article.SPECT utilizes standard nuclear

medicine cameras for which tomo-graphic methods are enabled. SPECTcapability is ubiquitous, as all nuclearmedicine departments in nearly everyhospital in the United States have suchcameras. The most common radioiso-topes used in SPECT are technetium99m (99mTc), iodine 123 (123I), thallium201 (201Tl), and indium 111 (111In).These radioisotopes are incorporated

Address correspondence toDr Robert S. Miletich, Universityat Buffalo, 105 Parker Hall, 3435Main St, Buffalo, NY 14214,[email protected] Disclosure:Dr Miletich serves on theeditorial board of the Journalof Neuroimaging and receivesresearch/grant support fromthe William E. Mabie, DDS,and Grace S. Mabie Fund.Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Miletich reports no disclosure.* 2016 American Academyof Neurology.

1636 www.ContinuumJournal.com October 2016

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

into molecules that trace a physiologicprocess. Physiologic processes that canbe measured in the clinical arena withSPECT include cerebral perfusion withexametazime Tc 99m or bicisate Tc99m, dopamine transporter (DAT)concentrations with ioflupane I 123,brain tumor uptake with thallous chlo-ride Tl 201, and CSF hydrodynamicswith diethylenetriamine pentaaceticacid (DTPA) In 111.PET requires specialized cameras,

as the physical process requires coin-cident detection of two high-energy511-keV photons. The only widelyavailable radioisotope for clinicalPET is fluorine 18 (18F), which, be-cause of its long half-life of 110 minutes,can be disseminated from regionaldistribution centers. Other radioiso-topes that may be used clinicallyhave much shorter half-lives, requir-ing on-site or local production; theseare not reviewed in this article. Theonly physiologic process that canbe assessed clinically by PET is cere-bra l g lucose metabol i sm withfludeoxyglucose F 18 (FDG).Neuromolecular imaging can mea-

sure some aspect of a pathologicprocess within the brain, but it canalso measure the physiologic effectsof that pathology on the functioningof cerebral parenchyma. Both types ofmeasurements provide useful diagnos-tic information. Because of the nearlystoichiometric relationship betweenregional neuronal synaptic activity,regional perfusion, and regional glu-cose metabolism, measuring the lattertwo provides information about re-gional brain activity. Currently neu-romolecular imaging can assay anumber of physiologic processes clin-ically. These assays can serve as bio-markers for the disease process.However, the diagnostic accuracy forany imaging biomarker is as depen-dent on how the biomarker is mea-

sured as it is on the biomarker itself.1Neuromolecular imaging is specializedtesting requiring specific expertise. Asmuch can be gained diagnostically fromthe visual interpretation of these im-ages by competent interpreters as fromstatistically rigorous methodology. Vi-sual interpretation is the typical experi-ence in the clinical realm.To review all potential applications

of neuromolecular imaging would re-quire review of all neurologic disor-ders; this article reviews the mostcommon indications for which clinicalreimbursement exists: dementia, braintumors, epilepsy, parkinsonism, cere-brovascular disease, and traumaticbrain injury (TBI). Table 12-1 lists indi-cations and the type of neuromolecularimaging used in these disorders.

DEMENTIAWith the aging populations of indus-trial and postindustrial societiesthroughout the world, age-related dis-orders, including neurodegenerativedisorders and specifically Alzheimerdisease (AD), are becoming publichealth epidemics. Effective therapiesfor neurodegenerative disorders havenot been developed because the basicpathophysiology of the disorders isnot understood. Clinical trials of newtherapies are confounded by the pres-ence of multiple diseases that showphenotypically similar clinical pre-sentations. Currently, the field issearching for biomarkers that canproperly diagnose these diseases, par-ticularly in the early stages whenabortive therapy will be most effective.Neuromolecular imaging provides thepotential for sensitive imaging bio-markers in dementia. Two indicationsfor neuromolecular imaging exist indementia: early diagnosis and differ-ential diagnosis.With the realization that neurode-

generative dementia has a prodromal

KEY POINTh Neuromolecular imaging

can measure someaspect of a pathologicprocess within the brain,but it can also measurethe physiologic effects ofthat pathology on thefunctioning of cerebralparenchyma. Bothtypes of measurementsprovide usefuldiagnostic information.

1637Continuum (Minneap Minn) 2016;22(5):1636–1654 www.ContinuumJournal.com


phase, a new diagnostic category calledmild cognitive impairment (MCI)gained wide acceptance. In the past30 years, the importance of neuro-imaging in the diagnosis of dementiahas also been accepted.2 As such, ajoint task force was convened by theNational Institute on Aging (NIA) andthe Alzheimer’s Association (AA) torevise the classic 1984 National Insti-tute of Neurological and Communica-tive Disorders (NINCDS)YAlzheimer’sDisease and Related Disorders Associa-tion (ADRDA) criteria for the diagnosisof AD in both dementia and MCI.3,4

These criteria now include core clinicalfeatures and biomarkers of the patho-physiologic process. The latter includestwo classes of evidence: biomarkers ofbrain amyloid-" deposition and bio-markers of neuronal degeneration orinjury. In imaging, positive PET amy-

loid imaging is a biomarker of brainamyloid-" deposition, and FDG-PEThypometabolism in the temporal andparietal cortices and MRI atrophy inthe temporal and parietal lobes arebiomarkers of neuronal degenerationor injury.Reviews have summarized diagnos-

tic accuracy for both perfusion SPECTand FDG-PET in the diagnosis of AD.Perfusion SPECT has been reported tohave sensitivities of 65% to 85% andspecificities of 72% to 87%. FDG-PETsensitivities of 75% to 99% and spec-ificities of 71% to 93% have beenreported. In general, PET has higherdiagnostic accuracy (an average of10% higher) than SPECT.5 Anotherreview essentially replicated thesefindings, with FDG-PET in AD versuscontrols showing 89% to 99% sensitiv-ities and 60% to 87% sensitivities.6

KEY POINTh Positive positron

emission tomographyamyloid imaging is abiomarker of brainamyloid-" deposition,and fludeoxyglucosepositron emissiontomographyhypometabolism in thetemporal and parietalcortices and MRI atrophyin the temporal andparietal lobes arebiomarkers of neuronaldegeneration or injury.

TABLE 12-1 Indications for Clinically Available NeuromolecularImaging Tests

Disorder Indications PET SPECTDementia Early diagnosis, differential

diagnosisFDG Bicisate,

exametazime

Brain tumors Grading, staging, tumorlocalization, mass lesiondiagnosis, tumor recurrenceversus treatment effect, therapyefficacy evaluation, malignantdegeneration diagnosis,prognostication

FDG Thallium

Epilepsy Episodic neurologic syndromediagnosis, localization ofseizure focus

FDG Bicisate,exametazime

Parkinsonism Early diagnosis, differentialdiagnosis

FDG Ioflupane,bicisate,exametazime

Cerebrovascular disease Cellular viability, cellularischemia

Bicisate

Traumatic brain injury Injury identification FDG BicisateFDG = fludeoxyglucose; PET = positron emission tomography; SPECT = single-photon emissioncomputed tomography.


PET and SPECT


Cerebral perfusion SPECT has variableefficacy in distinguishing AD fromother diseases, usually less effectivethan in comparisons of AD withhealthy controls. For distinguishing ADfrom healthy controls, exametazimeSPECT had 76% sensitivity and 85%specificity. These values were 80% and80% for frontotemporal dementia, 75%and 72% for vascular dementia, and70% and 76% for dementia with Lewybodies (DLB).7 SPECT had 79% accu-racy for distinguishing AD from otherdementing illnesses.6 Overall, the fewrecent publications on MCI have shownintermediate changes between demen-tias and healthy controls.8 Nonetheless,because neuromolecular imaging cap-tures the functional status of the brain,it has the capability for early diagnosis(Case 12-1) and differential diagnosis(Figure 12-2) in MCI.Three amyloid imaging markers,

florbetapir, flutemetamol, and flor-betaben, have been approved by theFDA, all tagged by 18F. Amyloid imag-ing has shown high correlation betweenregional amyloid tracer uptake and post-mortem insoluble amyloid deposits.Patients with AD have 50% to 90% highergray matter concentrations of amyloidtracers than controls. Amyloid imagingmay be useful in the differential diagnosisof dementia as amyloid accumulationsin frontotemporal lobar degenerationare low, similar to healthy controls.8However, amyloid imaging’s specificityis not fully defined at this time andmore research is needed. For instance,approximately 25% of patients withParkinson disease (PD) with dementiaand DLB had positive amyloid scans,similar to AD.12 Although the FDA hasapproved amyloid imaging agents,Medicare has not approved these stud-ies for reimbursement outside of theresearch setting. Although 80% to 100%sensitivity and specificity have beenreported using the amyloid imaging

research radiopharmaceutical carbon11Ylabeled Pittsburgh Compound B(11C-PiB), this diagnostic accuracy isdependent on age as an age-related in-creased prevalence of amyloid traceruptake exists, with up to 40% of asymp-tomatic people over 70 years of agehaving high cortical PiB uptake.6,13

Amyloid imaging also shows little sig-nificant change over time and is poorlycorrelated with clinical progression ofdisease, in contrast to atrophy on MRIand cerebral perfusion and metabo-lism worsening with disease progres-sion. A potential application of amyloidimaging is prognosticating AD develop-ment in patients with MCI or even inasymptomatic individuals, but this hasnot been established.13 Given the un-certainties of the pathophysiologic pro-cess of AD, it remains unclear whatthe diagnostic certainty for amyloid im-aging will be. Although it is likely thatamyloid imaging will have very goodnegative predictive value, a likely poorpositive predictive value may hinder itsusefulness.It has been proposed that examina-

tion of the dopamine system withDAT agents can help in the differentialdiagnosis of AD from DLB or PDdementia,12 but few studies have beenpublished at this time.A comprehensive meta-analysis re-

view of literature from January 1990 toMarch 2010 that examined diagnosticbiomarkers for AD, including CSF,clinical features, MRI, SPECT, andFDG-PET, showed that as comparedto controls without dementia, FDG-PET had the highest area under thereceiver operating characteristic curve(AUROC) at 0.96, with 90% sensitivityand 89% specificity. FDG-PET was alsobest in discriminating AD from otherdementias, with 0.91 AUROC, 92%sensitivity, and 78% specificity. Theperformance of SPECT, MRI, and CSFphosphorylated tau concentrations

KEY POINTh Patterns of central

nervous systemdysfunction shown onneuromolecular imagingusually develop early inthe disease course ofdementia, facilitatingearly diagnosis.



were similar to one another, withAUROC of 0.85 to 0.86.14

AD is a global brain disorder. Theoften-stated criteria for making the

neuromolecular imaging diagnosis ofAD has been hypometabolism or hy-poperfusion in the temporal and parie-tal cortices. Although this certainly is

Case 12-1A 67-year-old man developed confusion postoperatively following endovascular repair of anabdominal aortic aneurysm. The confusion cleared, but he and his wife noted short-term memoryproblems that progressively worsened over the subsequent year. He also developed difficulties withcalculations and multitasking. His wife noted that he no longer did well under pressure situations. He wasa retired attorney and remained independent in activities of daily living. Past medical history wassignificant for hypercholesterolemia, hypertension, and vitamin B12 and vitamin D deficiencies. Allfour disorders had been medically corrected or controlled by the time of the fludeoxyglucose positronemission tomography (FDG-PET) scan; MRI showed moderate diffuse atrophy. He had recently scored25 out of 30 on the Mini-Mental State Examination (MMSE) and had been diagnosed with amnesticmild cognitive impairment. FDG-PET/CT revealed mild diffuse atrophy on CT and a selective pattern ofassociation cortex hypometabolism, worst posteriorly. Severe decreases were shown in the lateralparietal cortex (Figure 12-1A) and medial parietal cortex (Figure 12-1B). Severe hypometabolism in theinferior temporal cortex, moderate hypometabolism in lateral temporal cortex, and mild decreasesin frontal cortex were also present.

Comment. This case demonstrates the use of FDG-PET/CT in supporting the diagnosis of prodromalAlzheimer disease in mild cognitive impairment. Recent literature analyzing diagnostic testing, diseaserisk factors, and postmortem pathology have revealed that besides Alzheimer disease, mild cognitiveimpairment can result from multiple other disorders, individually or as comorbidities.9Y11 FDG-PET/CTrevealed association cortex dysfunction in a pattern unique to Alzheimer disease. This pattern had noCT correlate in that the atrophy seen was diffuse.

FIGURE 12-1 Imaging of the patient in Case 12-1. Fludeoxyglucose positron emissiontomography (FDG-PET)/CT with fused CT in gray scale and PET in color scalein the transverse (A) and sagittal (B) planes. Severe hypometabolism can be

seen in the medial parietal cortex (A, down-pointing arrow; B, arrow), and lateral parietalcortex (A, horizontal arrows). Bright intensity or hot coloration (white, yellow) in PETindicates high tracer localization and thus higher amounts of glucose metabolism. Lowintensity or cold coloration (black, orange) indicates low amounts.


PET and SPECT


needed, it is an inadequate characteri-zation of the array of changes that areseen functionally on neuromolecularimaging in AD. These findings includea widespread, but posteriorly domi-nant, asymmetric association cortexhypofunction with relative preservationof function in the primary cortices.Many disorders cause decreased func-tion of the association cortex, which iscalled the global brain impairmentpattern. Many global brain impairmentsubpatterns exist, which help distin-guish between the different disorders.

In the previously mentioned literature,neuromolecular imaging specificitiesare often lower than the sensitivities.This is because other disorders have apredilection for affecting the temporaland parietal cortices. In the author’sclinical practice, the biggest confounderis small vessel disease.15

BRAIN TUMORSApproximately 50,000 people are diag-nosed with primary brain tumors inthe United States annually and140,000 with metastatic brain tumors.

KEY POINTSh Each dementing illness

has its own patternof central nervoussystem dysfunction onneuromolecularimaging, facilitatingdifferential diagnosis.

h The typical imagingpattern for Alzheimerdisease is a posteriorlydominant asymmetricassociation cortexhypofunction, worst intemporal and parietalcortices, with importantinvolvement of themedial parietal cortex.Function is betterpreserved in primarycortex and subcorticalgray matter structures.

FIGURE 12-2 Two examples of the neurodegenerative patterns of Alzheimer disease (A, B)and frontotemporal lobar degeneration (C, D) in cerebral perfusion bicisatesingle-photon emission computed tomography (SPECT) from transverse

(A, C) and sagittal planes (B, D). Regions of maximal involvement in the medial parietalcortex (A, red arrow; B, arrow), lateral temporal and parietal cortices (A, white arrows),medial frontal cortex (D, arrow), and polar and lateral frontal cortex (C, arrows) can be seen.Images are of a 70-year-old woman (A, B) and an 85-year-old man (C, D) both with a 1-yearhistory of short-term memory impairment. Both had been diagnosed with mild cognitiveimpairment and maintained intact affairs of daily living. Bright intensity or hot coloration(white, yellow) in SPECT indicates high tracer localization and thus higher amounts of cerebralperfusion. Low intensity or cold coloration (black, purple, blue-green) indicates low amounts.



Gliomas were the first human neo-plasm for which the diagnostic utilityof FDG-PET was shown by theGiovanni Di Chiro group in 1982.15The foundation for this was laid byOtto Warburg in the 1930s, whoshowed increasing glucose utilizationand glycolysis in many different bodycancers with increasing malignancyand anaplasia. This is now coined theWarburg theory, and it remains thebasis for the use of FDG-PET inoncology. Having a noninvasive mea-sure of the biological behavior oftumors is critical for rational manage-ment of these disorders.The indications for FDG-PET in

brain tumors include tumor grading,tumor staging, tumor localization, thedifferential diagnosis of cerebral masslesions, distinguishing between tumorrecurrence versus treatment effect,therapy efficacy evaluation, early diag-nosis of malignant degeneration, andprognostication.15,16 The author’s ex-perience is that FDG-PET is a usefultechnique for all of these indications.Therapy must be titrated for thetumor grade. Targeted therapies re-quire knowledge of tumor locationand spread. MRI is very sensitive tostructural changes but often is notspecific and may not distinguish whereneoplasm actually resides within a le-sion bed. It often cannot distinguishtissue inflammation or necrosis fromneoplasm, a distinction needed fortherapy evaluation or planning. Low-grade gliomas quite often undergomalignant degeneration to a higher-grade tumor. Timely diagnosis of suchtransformation can improve outcomes.Finally, because FDG-PET is an assay ofhigh fidelity for the tumor’s biologicalbehavior, a more accurate prognosis isthus provided.It is true that FDG-PET is not easy

to interpret given that the milieu isthe cerebrum, the most metabolically

active organ in the body. It is easy tomisinterpret these studies in the ab-sence of sufficient training and expe-rience. In the management of patientswith brain tumors, MRI remains thestandard imaging modality, in particu-lar using contrast-enhanced sequences.These have high sensitivity but oftenlow specificity. This often leads to thediagnostic conundrum of assessingthe presence of treatment effect ver-sus tumor recurrence in patients withknown brain tumors. This is the mostcommon indication for FDG-PET inthe author’s experience. As such, theinterpretation of FDG-PET requiresmultimodal cross-correlation. Morediagnostic information is extractedfrom PET by correlating it to MRI.FDG-PET is complementary to MRIin that it adds value in defining thebiological behavior of the lesion field.Much of the formative work on the

efficacy of FDG-PET in brain tumorswas published decades ago by the DiChiro National Institutes of Healthgroup. More recent work has replicatedthis earlier work and has shown thehigh diagnostic accuracy of FDG-PETfor grading tumors, assessing tumorprogression, and distinguishing tumorrecurrence versus treatment effect inpreviously treated patients with braintumors.17 For example, using tumorFDG uptake that is greater than orequal to 0.6 times the values in graymatter or 1.5 times the values in whitematter resulted in 94% sensitivity and77% specificity for distinguishing high-grade from low-grade neoplasms.16 Forthe diagnosis of tumor recurrence ver-sus treatment effect, sensitivities of80% to 86% and specificities of 40% to88% have been reported in the litera-ture (Case 12-2).16 This wide rangeof reported values may be becauseof variability of interpretative skills, asdiscussed previously. By characteriz-ing the biological behavior of brain

KEY POINTSh The biological behavior

of tumors is reflectedin their glucosemetabolic profile.

h The interpretation offludeoxyglucose positronemission tomographyrequires multimodalcross-correlation.


PET and SPECT


Case 12-2A 57-year-old woman who underwent resection of a left occipital lobe glioblastoma multiforme 2 yearspreviously, followed by concurrent chemoradiation and 24 cycles of adjuvant temozolomide, was found tohave a new contrast-enhancing lesion onMRI 2months after completion of her last cycle of temozolomide.Fludeoxyglucose positron emission tomography (FDG-PET)/CT was requested for evaluation of tumorrecurrence versustreatment effect. PET(Figures 12-3A and12-3C) clearly revealeda 7-mm hypermetabolicfocus at the MRIcontrast-enhancing site(Figure 12-3D). CTshowed a faint corticalhypoattenuation(Figure 12-3B). Thesurrounding cortex washypometabolic. Thesefindings were consistentwith tumor recurrencein the right medialparietal cortex,contralateral to theoriginal neoplasm.Stereotactic radiosurgerywas planned.Comment. This case

illustrates a number ofpoints. Small lesionscan be assessed withmodern PET/CTcameras because ofimproved spatialresolution. PET is rarelyread in isolation of anyother modalities. Toextract the maximumamount of diagnosticinformation fromfunctional imaging,cross-correlation tostructural imaging isneeded. Theinterpretation ofbrain tumor studiesis based both ontumor bed changesand the effects on thecerebral parenchyma.

FIGURE 12-3 Multimodal imaging of the patient in Case 12-2 with fludeoxyglucosepositron emission tomography (FDG-PET) (A), CT (B), fused PET and CT(C ), and gadolinium-enhanced T1-weighted MRI (D). A 7-mm focus of

hypermetabolism is seen (A, C, arrows) at the site of MRI enhancement (D, arrow). Mildhypoattenuation can be seen at this site on CT (B, arrow). This focus is surrounded byhypometabolic cortical ribbons. The findings are consistent with recurrence of high-gradeglioma and diaschisis of neighboring gray matter. In panel A, darker intensity indicateshigher amounts of glucose metabolism. In panel C, bright intensity or hot coloration (white,yellow) indicates higher amounts of glucose metabolism.



tumors, FDG-PET provides prognosticinformation. For example, high FDGuptake in glioblastomas was associ-ated with a 29% 1-year survival, whilelow FDG uptake was associated with a94% 1-year survival.18 This essentiallyreplicates the findings reported bythe Di Chiro group 30 years ago.Another camp of opinion exists in

the literature that denigrates the ef-fectiveness of FDG-PET in providinguseful clinical management informa-tion in brain tumors. This group hasdiscouraged use of FDG-PET for as-sessment of glioblastoma progression19

or for assessing tumor progressionversus treatment effect following ra-diosurgery.20 These negative pro-nouncements may be related to theinterpretative difficulties posed byevaluating glucose metabolism withinthe brain. FDG-PET diagnosis is notmade simply by the presence or ab-sence of tumoral FDG. It is a multi-modal cross-correlative evaluation thatassesses magnitude, pattern, morphol-ogy, location, and even temporal be-havior of this uptake relative to thestructural changes shown on MRI. Alsocritical in this evaluation are the effectson the surrounding parenchyma. Highdiagnostic accuracy exists with theproper interpretative scheme.Because of reported difficulties

with FDG, a movement for imagingbrain tumors with radioactive aminoacids has developed, primarily inEurope. Given the greater contrast ofuptake between neoplasm and brainparenchyma, imaging with radioactiveamino acids is easier to read. How-ever, the grading capability of theseimages has been questioned in theliterature.21 In the opinion of thisauthor, with an experienced neuro-molecular imager, FDG provides highdiagnostic accuracy. No other PET andSPECT tracers have been definitivelyshown to be diagnostically advanta-

geous as compared to FDG,18 and noPET agents are FDA approved foramino acid imaging.SPECT with [201Tl]thallous chloride

is also a useful neuromolecular imagingtechnique for brain tumors. Althoughthe sensitivities and specificities are notas high as those of FDG-PET, they havebeen reported in the 80% range, indi-cating a useful diagnostic test. SPECTwith [201Tl]thallous chloride has beenrecommended for assessment of glio-blastoma progression.19 Thallium istreated as a potassium analogue bythe blood-brain barrier and, as such,gains entry into the brain only withblood-brain barrier disruption. Thissimplifies interpretation, as it becomesa matter of hot spot identification.

EPILEPSYEpilepsy affects 1% to 2% of the popu-lation. At least 30% of patients withepilepsy will fail to adequately respondto antiepileptic drugs. Surgical treat-ment remains an option in these pa-tients. Two main indications exist forneuromolecular imaging in epilepsy.One is to assist in the differentialdiagnosis of episodic syndromes thatmay or may not be due to epilepsy. Thesecond is to help localize the epilepto-genic zone in candidates for surgicalresection of a seizure focus. The firstindication has become an integral partof the author’s clinical practice; unfor-tunately, no well-characterized pub-lished data exist on this use ofneuromolecular imaging. However,the presurgical evaluation indicationis well established.22Y24Neuromolecular imaging has proven

usefulness in the noninvasive iden-tification of the epileptic zone in can-didates for resective epileptic surgery.This localization requires a multi-modal investigation that includes elec-trophysiology, structural imaging, andfunctional imaging and may include


has proven usefulnessin the noninvasiveidentification of theepileptic zone incandidates for resectiveepileptic surgery.


PET and SPECT


invasive neurosurgical diagnostic tech-niques. Interictal FDG-PET and bothictal and interictal SPECT are nowroutinely performed in surgical epilepsycenters throughout the world. Neuro-molecular imaging has high sensitivity,with ictal SPECT at 96%, interictalSPECT at 44%, postictal SPECT at 75%,and interictal FDG-PET on modernequipment up to 90% for temporal lobeepilepsy and 67% for extratemporalepilepsy (Case 12-3).16The combination of interictal and

ictal SPECT, with or without MRI,using standard computer imagingtechnology increases the diagnosticaccuracy of epileptic zone localization.This image processing is done atsurgical epilepsy centers throughoutthe world. Many different systems havebeen developed. Subtraction ictalSPECT coregistered to MRI (SISCOM),developed at the Mayo Clinic, is themost widely known, but other method-ologies exist.25 During ictus, seizurefoci demonstrate hyperperfusion. Thepurpose of combining the ictal andinterictal SPECT images is to identifythis site of ictal-activated hyperperfu-sion. This is done by subtracting theinterictal image volume from the ictalimage volume. The difference is ictalactivation. All of these techniquesrequire three-dimensional registrationof image sets, followed by propor-tional normalization, which then allowsalgebraic manipulation of the interictaland ictal images. The final product isparametric images of ictal activation(Figures 12-4C and 12-4D). Even ictaldeactivation parametric images can becreated. Examining both ictal activationand ictal deactivation parametric im-ages can provide diagnostic informa-tion. The greatest challenge inperforming ictal SPECT is in injectingradiotracer as close to the time of sei-zure onset as possible. Four differentpatterns of ictal activation and deactiva-

tion can be seen based on the timing ofthe bicisate injection relative to seizureonset: focal ictal activation, lobar oreven more widespread ictal activation,widespread ictal deactivation, and focalictal deactivation. The first has thegreatest fidelity for epileptic zone char-acterization, but diagnostic informationis present in each pattern.For many patients, noninvasive

techniques may be sufficient to guidesurgery for the site of surgical resec-tion. However, if localization is notpossible, neuromolecular imaging maybe able to regionalize or lateralize theepileptogenic zone, which can mini-mize the extent of subsequent invasivediagnostic techniques. Neuromolecularimaging is particularly useful when MRIis either normal or shows multiplelesions, any one of which could be theepileptic zone.Neuromolecular imaging is also use-

ful in epileptic syndromes, such as inepileptic spasms with the EEG patternof hypsarrhythmia. The underlying pa-thology is variable and can be due toeither multifocal or unifocal corticallesions, resection of which may cureor control epilepsy.24 Other syndromeswith similar considerations are tuber-ous sclerosis, Sturge-Weber syndrome,various congenital malformations, andeven Rasmussen encephalitis. The goalin all of these is to identify a resectableepileptic zone.

PARKINSONISMThe clinical diagnosis of PD is incor-rect 20% of the time.26 Misdiagnosis iseven greater for the atypical parkinso-nian syndromes. This differential diag-nosis problem arises because of thelarge number of disorders causingparkinsonism.27 These include theLewy body diseases of PD and DLB;the atypical parkinsonian syndromesmultiple system atrophy (MSA), pro-gressive supranuclear palsy (PSP),

KEY POINTSh Ictal single-photon

emission computedtomography and interictalpositron emissiontomography can helplocalize seizure foci in thepresurgical evaluationof candidates forepilepsy surgery.

h A computer-generatedcombination of ictalsingle-photon emissioncomputed tomography(SPECT), interictalSPECT, and MRI oftenprovides preciselocalization ofseizure foci.

h The greatest challengein performing ictalsingle-photon emissioncomputed tomographyfor imaging in epilepsyis in injecting radiotraceras close to the timeof seizure onsetas possible.



Case 12-3A 54-year-old woman with increasing frequency of seizures presented as a candidate for epilepsysurgery. Her symptomatology was stereotypic, with an aura of fear followed by loss of contactwith her right hand, oral automatisms, and left hand dystonic posturing, all lasting 2 to 3 minutes.MRI revealed no temporal structural abnormality, but showed small occipital areas ofcortical dysplasia. EEG revealed interictal sharp waves and intermittent rhythmic deltaactivity in the righttemporal region.Fludeoxyglucosepositron emissiontomography (FDG-PET) intransverse (Figure 12-4A)and coronal planes(Figure 12-4B) revealedright temporalhypometabolism inboth allocortex andneocortex. Ictalactivation images(Figures 12-4C and12-4D) revealed focalictal activation in theright anterior medialtemporal lobe. Invasiveelectrophysiologicstudies were deemedunnecessary given thecorrelative diagnosticinformation.Comment. This case

illustrates the key roleneuromolecular imagingplays in the presurgicalevaluation of patientswith epilepsy. Whenall diagnostic informationis congruent, expensiveand invasive diagnostics,such as subduralelectrode grids or depthelectrodes, canoften be avoided.

FIGURE 12-4 Neuromolecular imaging of the patient in Case 12-3 includes ictalfludeoxyglucose positron emission tomography (FDG-PET) (A, transverse;B, coronal), and ictal activation images (C, transverse; D, transverse, 5 mm

dorsal to C). There is glucose hypometabolism in the right temporal lobe (arrows, A, B).The ictal activation images were generated from ictal and interictal bicisate single-photonemission computed tomography (SPECT) images. Both SPECT images are put into thesame stereotactic space of the MRI, followed by proportional normalization, which thenallows subtraction of the interictal image volume from the ictal image volume, leavingthose regions that show increased perfusion due to ictus. The ictal activation images helpto identify the location of seizure foci. The only coloration in panel C and panel D indicatesthe ictal activation. The processed SPECT is registered to a fluid-attenuated inversionrecovery (FLAIR) sequence MRI, which is displayed in gray scale. In panel A and panel B,bright intensity or hot coloration (red, yellow) in PET indicates high tracer localization andhigher amounts of glucose metabolism. Low intensity or cold coloration (purple, blue)indicates low amounts. In panel C and panel D, red and orange indicate high ictalactivation. No color indicates no ictal activation.


PET and SPECT


corticobasal degeneration, and othertypes of frontotemporal dementia;and the secondary parkinsonian syn-dromes caused by drugs, vasculardisease, or normal pressure hydro-cephalus. Even tremor disorders, suchas essential tremor, can enter thedifferential diagnosis.The indications for neuromolecular

imaging include the early diagnosisand differential diagnosis of parkin-sonism. Currently, four radiotracersare clinically available in the UnitedStates with proven utility for these in-dications. These include exametazimeand bicisate for cerebral perfusionSPECT, ioflupane for DAT imaging,and FDG for regional glucose metab-olism. Each neuromolecular imagingtype will show changes that reflect ahypodopaminergic state. The perfu-sion and metabolism tracers will alsoshow regional dysfunction from dis-ease involvement in other neuronalelements. The deficiency of dopa-

mine, induced in earlier stages of theLewy body diseases, will result inhyperperfusion or hypermetabolismwithin the striatum (Figure 12-5).This hyperfunction may also be seenfrom neuroleptic medication. All theother parkinsonism disorders typi-cally cause hypofunction in the stria-tum. Only ioflupane I 123 provides adirect measure of the loss of dopamineinnervation to the striatum.The differential diagnostic utility of

neuromolecular imaging results fromthe different patterns seen for differ-ent disorders. This is the principleused in the clinic for visual interpreta-tion of these studies. It also underliesthe published neuromolecular imag-ing literature. For validation, thesepatterns must be compared to somegold standard. Very few studies haveused the best gold standard, which ispostmortem tissue confirmation. Inlieu of tissue diagnosis, most studieshave used consensus clinical criteria

FIGURE 12-5 Two different 65-year-old men with stage 3 Parkinson disease, one scannedwith fludeoxyglucose positron emission tomography (FDG-PET) (A) and theother with bicisate single-photon emission computed tomography (SPECT) (B).

Both were withdrawn from dopaminergic therapy prior to neuromolecular imaging. Mildhypermetabolism (A, arrows) and hyperperfusion (B, arrows) can be seen in the striatum.This is often worse in the posterior inferior lenticular nuclei (A). This hyperfunction is absentin the neurodegenerative atypical parkinsonian syndromes, but it is seen in dementia withLewy bodies. Bright intensity or hot coloration (red, yellow) indicates high tracer localizationand thus higher amounts of glucose metabolism (A) and perfusion (B). Low intensity or coldcoloration (black, blue) indicates low amounts.



developed by professional organiza-tions, along with detailed patientfollow-up for 0.5 to 3 years followingthe imaging. Such methodology hasproven adequately valid upon directexamination.28 There have also beentwo types of image analysis in the liter-ature, visual examination of images by anexpert versus applied computer method-ology. The former replicates what occursin the clinic, while the second is a fieldin development. Not surprisingly, thereported findings of the two methodol-ogies are very similar because both beginwith the same information: the images.With clinical diagnosis consensus

criteria as gold standard, FDG-PET isable to distinguish PD from atypicalparkinsonian syndromes with greaterthan 90% accuracy, using expert visualanalysis.27,29,30 Visual analysis of FDG-PET can also discriminate between theatypical parkinsonian syndromes MSA,PSP, and corticobasal degeneration,with greater than 75% sensitivity and90% specificity overall.27,31 Concor-dance with clinical diagnosis wasreported of 80% for MSA, 93.3% forPSP, and 100% for corticobasal degen-eration in 136 parkinsonian patients.29

Another study using similar method-ology reported sensitivities/specific-ities of 77%/97% for MSA, 74%/95%for PSP, and 75%/92% for corticobasaldegeneration in 95 parkinsonian pa-tients.30 The one recent study that usedpostmortem tissue diagnosis as thegold standard reported concordanceof FDG-PET with tissue diagnosis inseven patients with PSP and one patientwith corticobasal degeneration.32 Morestudy is needed on this, particularlywith regard to concordance to post-mortem gold standards, but the find-ings to date support the usefulness ofFDG-PET in parkinsonism diagnosis.Little has been published on the roleof perfusion SPECT in parkinsonism in

the past 5 years, with this literaturebeing mature but indicating a role forperfusion SPECT in these disorders.

Beyond visual interpretation, anumber of studies have used comput-erized methods for analyzing FDG-PET images of parkinsonism. Thesemethods have included voxel-basedmethods in which statistical analysisis applied to each volume element, orvoxel, of the image, comparing theresults to a database of normal sub-jects.29 Other techniques have appliedmultivariate analyses to define neuro-nal networks based on how brainregions covary together.33 Althoughthere have been reported findings ofa similar nature as that reported withvisual analysis, it is the author’s opin-ion that this computerized analysisfield needs to mature further beforethere can be any consideration for itsusefulness in the clinical arena.Ioflupane I 123 has been shown by

histopathology in animals and humansto bind to the DAT on presynapticdopamine terminals. Loss of this bind-ing is a surrogate marker of the loss ofnigrostriatal terminals.34,35 A high cor-relation (R = 0.65) exists between DATimaging and the density of dopamineneurons in the substantia nigra. Par-kinsonism can be a difficult differentialdiagnosis.27 The identification of lossof DAT and the pattern of that losshelp to distinguish neurodegenerativeparkinsonism from secondary parkin-sonism caused by drugs and even fromtremor disorders such as essentialtremor (Figure 12-6). DAT imagingusing visual analysis has been reportedto help distinguish vascular parkinson-ism from PD with a 94% accuracy.36Each neurodegenerative process canhave its own pattern, creating thepotential to distinguish between them.Atypical parkinsonian syndromes andearly DLB tend to have more homog-enous and more symmetric involve-ment of the caudate and putamen than

KEY POINTSh Differential diagnostic

information forparkinsonism is providedby the pattern of striataland cortical uptakeof neuromolecularimaging tracers.

h The identification of lossof dopamine transporterand the pattern of thatloss help to distinguishneurodegenerativeparkinsonism fromsecondary parkinsonismcaused by drugs andeven from tremordisorders such asessential tremor.


PET and SPECT


PD. PD tends to have a posterior toanterior gradient of improving uptakewithin the striatum. However, a consid-erable overlap exists in the intrastriatalpatterns, making distinction from otherneurodegenerative parkinsonism diffi-cult.31 Given the phenotypic overlap ofDLB and AD, DAT imaging has poten-tial usefulness in this distinction. DATimaging has 87% sensitivity and 94%specificity in distinguishing DLB fromother dementias or controls.

CEREBROVASCULAR DISEASESPECT and PET are useful techniquesfor the evaluation of hemodynamicreserve in patients with severe cere-brovascular disease. SPECT allows as-sessment of cerebral perfusion. Usingoxygen 15 (15O) tracers, PET can mea-sure cerebral blood flow, cerebral bloodvolume, and oxygen extraction frac-

tion; the latter is a particularly goodindicator of whether tissue is criticallyhypoperfused (the presence of in-creased oxygen extraction fractionmeans that the tissue is not receivingsufficient blood to its energy require-ments). Three stages of hemodynamiccompromise have been defined exper-imentally using 15O PET tracers for mea-suring regional cerebral blood flow,blood volume, and oxygen extractionfraction.37 Bicisate SPECT is capableof defining these three stages as well.Stage 0 is the absence of abnormalitydue to presence of collateral flow chan-nels. In stage I, a tissue vasodilatationrestores regional flow to normal butresults in increased regional bloodvolume and decreased vascular reserve.Stage II has increased blood volume,decreased vascular reserve, and de-creased blood flow or perfusion.

KEY POINTSh Perfusion and

metabolism imagingindirectly demonstratethe hypodopaminergicstate by showing itssynaptic consequences.

h Dopamine transporterimaging directlydemonstrates thehypodopaminergicstate by showing lossof dopaminergicnerve terminals.

FIGURE 12-6 Ioflupane I 123 imaging of the dopamine transporter. A, Imaging of a55-year-old man with a 5-year history of worsening hand tremor,worse on the right. There is normal ioflupane distribution through the

cerebrum, making essential tremor the likely diagnosis. B, Imaging of a 39-year-oldwoman with a 1-year history of worsening tremors. Two findings are noted.Diminished contrast between the striatum and the rest of the brain due to decreasedstriatal uptake; these decreases are worse in the putamen, particularly posteriorly,than in the caudate. These findings are consistent with neurodegenerativeparkinsonism. Although Parkinson disease is the most likely diagnosis, other atypicalparkinsonian syndromes, such as multiple system atrophy, progressive supranuclearpalsy, corticobasal degeneration, or frontotemporal dementia cannot be entirelyruled out. Bright intensity (white) indicates high tracer localization and thus higherdopamine transporter concentrations. Low intensity (black) indicates low amounts.



Cerebral perfusion SPECT involvesthe simultaneous assessment of twophysiologic processes, neuronal activ-ity and the state of the vascular tree.Techniques to disentangle the cere-bral perfusion SPECT signal into neu-ronal function versus vascular diseaseinduce a dilatation in responsive vas-cular beds by interventions that pro-voke tissue acidosis. Available optionsare the carbonic anhydrase inhibitoracetazolamide, which induces a meta-bolic acidosis, and inhalation of car-bon dioxideYenriched gas, whichinduces a respiratory acidosis. Thepresence of compromised vascular re-serve can be determined by compar-ing the perfusion before and after thevasodilatory challenge. Because vesselsin ischemic territories will already bedilated, the vasodilatory challenge willresult in lesser increase in perfusion

in that area, indicating diminished vas-cular reserve (Figure 12-7). The in-crease in perfusion after the challengeis variable; in the author’s experience, itis between 10% and 50%. This amountof activation is sufficient for diagnos-tic purposes.The two main perfusion SPECT

radiopharmaceuticals currently in useare exametazime Tc 99m and bicisateTc 99m. Their cellular uptake mecha-nisms are different, which results insignificantly different imaging capa-bilities. Only bicisate has a braincel lYspecif ic uptake mechanism,based on one or more esterases onlyexpressed within brain cells. The mainuptake and retention mechanism forexametazime is glutathione chelation.Glutathione is present in all cells ofthe body, including inflammatory cells,meningeal cells, and fibrocytes. Most

FIGURE 12-7 Imaging of a 49-year-oldmanwho had undergone sacrifice of the left internalcarotid artery for aneurysms that could not be treated endovascularly.Subsequently, the patient had two episodes of right arm shaking. The differential

diagnosis was transient ischemic attacks versus seizure. The possible need forextracranial-intracranial bypass was discussed. Only heterogeneous multifocal white matterhypoperfusion is evident on the rest images of the bicisate vascular reserve cerebral activationperfusion single-photon emission computed tomography (SPECT) study (A), consistent withsmall vessel disease. However, after administration of the stress agent acetazolamide, aclear-cut middle cerebral artery territory hypoperfusion is evident (B, arrow), indicatingvascular reserve compromise. It was likely the right arm shaking episodes were transientischemic attacks. In the awake resting state, collateralization and middle cerebral artery treevasodilatation are able to compensate for the hindered internal carotid artery flow. Thesecompensations may not be adequate in states of decreased perfusion pressure (eg, sleep).Bright intensity or hot coloration (white, yellow) indicates high tracer localization and thushigher amounts of perfusion. Low intensity (black, purple, blue) indicates low amounts.

KEY POINTh Cerebral perfusion

single-photon emissioncomputed tomographyinvolves the simultaneousassessment of twophysiologic processes,neuronal activity and thestate of the vasculartree. Techniques todisentangle the cerebralperfusion single-photonemission computedtomography signal intoneuronal function versusvascular disease inducea dilatation in responsivevascular beds byinterventions thatprovoke tissue acidosis.


PET and SPECT


of the earlier literature in acute strokethat showed low diagnostic accuraciesfor perfusion SPECT used exametazime.Because of the difference of brain celluptake mechanisms, brain cell viability,and, thus, reversible ischemia, is onlyreliably revealed by bicisate.In acute stroke, two tissues are

threatened: the ischemic core andthe surrounding tissue, the penumbra.Although the fates are initially uncer-tain, much of the ischemic core will goon to infarction while the ischemicpenumbra retains the potential forsalvage. Stroke evolution over time isin major part related to propagation ofinfarction within these threatened tis-sues. SPECT with either exametazimeor bicisate within the first 8 hours ofacute stroke presentation has a positivepredictive value of 90%, with reportedsensitivities of 61% to 74% and specific-ities of 88% to 98%.37 Twenty patientswere evaluated with bicisate SPECTprior to IV recombinant tissue-typeplasminogen activator (rtPA) therapy.38

Brain regions with bicisate concentra-tions that were 15% to 53% that of thecontralateral side went on to infarctdespite rtPA therapy. Values of 45%to 83% indicated reversible ischemiasalvageable from death followingtreatment. Values of 45% to 52%uptake were taken as the thresholdfor viability and therapy triage.38

Exametazime-SPECT 1 hour followingrtPA therapy in 35 patients was alsopredictive of outcome, with hypoper-fusion associated with poor outcome.39

Bicisate SPECT can also be used in theacute setting to distinguish a transientischemic attack from an evolvingstroke by using a cutoff uptake valueof 70% or greater relative to the ho-mologous region of the contralateralhemisphere.40 In the subacute phaseof stroke, bicisate retains its advantageover exametazime by its specificity ofcell uptake mechanism. Exametazime

may show higher apparent perfusionthan bicisate because exametazime istaken up not just by brain cells but alsoby other cell types, such as inflam-matory cells, fibrocytes, and other mes-enchymal elements.SPECT might also be useful in the

evaluation of patients with suspectedvascular cognitive impairment. Currently,the diagnosis of vascular dementia orvascular cognitive impairment issupported by MRI, which identifiestissue structural injury, such as gray orwhite matter infarcts or white matterhyperintensities. These methods arenot sensitive to the presence of activeischemia before tissue injury, particu-larly that from small vessel disease.Measuring cerebral hemodynamic re-serve may facilitate the etiologic diag-nosis of cognitive impairment and helpto address risk factor management.However, this application for SPECTremains mostly investigational.41

TRAUMATIC BRAIN INJURYIn the past few years, the public hasbeen made aware of the role of re-petitive TBI in causing long-term mor-bidity in athletes of contact sports.This clinical syndrome, called chronictraumatic encephalopathy, has mostdramatically been demonstrated informer National Football Leagueplayers.42 However, TBI occursthroughout the population by variousmeans, including motor vehicle acci-dents, assaults, and even falls in thosewith or without gait impairment. Fol-lowing concussion or mild TBI, patientsoften are left with persistent symp-toms that profoundly compromise theirquality of life. CT and MRI often showno abnormalities.These injuries occur due to differen-

tial brain acceleration and momentumrelative to other tissues. Concussionresults from rotational or angular ac-celeration of the brain. Contusion is



a more forceful process, with actualmacroscopic schism of tissue. Thebrain impacts surrounding structures,typically the inner table of the skull,but the meninges are also involved.Shear or strain forces also propagatewithin the brain itself, again due to adifferential acceleration or momen-tum. White matter shear or straininjuries are one example. Most ofthese brain injuries are contrecoupinjuries. Neuromolecular imaging showsdecreased perfusion and metabolism atthe sites of brain injury, typically in thepolar and orbital frontal and temporallobes, the dorsal vertex of the frontaland parietal lobes where glide contu-sions occur, and, less commonly, in theperisylvian regions and inferior cerebel-lum. However, injury can potentiallyoccur anywhere in the cerebrum.

Bicisate SPECT and FDG-PET have highsensitivity for detecting sites of injurybecause their imaging signal requiresintracellular uptake of radiopharma-ceuticals. Absence of cells or cellulardysfunction results in decreased radio-pharmaceutical localization. Regionalchanges have been concordant withneuropsychological findings.43 SPECToutperformed both CT and MRI andhad high positive predictive value andnear 100% negative predictive valuefor the continued presence of clinicalsymptoms at 3-month intervals after theinjury.44 In the author’s experience,the location and pattern of physio-logic changes on PET and SPECT inmild TBI include wedge defects andregional decreases incongruent withlevels of perfusion or metabolism else-where in the cerebrum (Figure 12-8).

FIGURE 12-8 Imaging of a 22-year-old man with persistent cognitive and affectivedifficulties following a motor vehicle accident 1.5 years ago. His schoolperformance had deteriorated, and he was anxious with a depressed

mood, not typical for him prior to the accident. A, Bicisate single-photon emissioncomputed tomography (SPECT) shows hypoperfusion in the orbital frontal cortices,where subtle parasagittal wedge defects are also seen (arrows). B, Fluid-attenuatedinversion recovery (FLAIR) MRI shows a long T2 lesion in the right inferior temporallobe (arrow) and no other findings. Bilateral inferior temporal cortex hypoperfusion canalso be seen where a wedge defect is evident at the site of long T2 (C, arrow). In panelA and panel C, bright intensity or hot coloration (white, yellow) in SPECT indicates hightracer localization and thus higher amounts of perfusion. Low intensity or coldcoloration (purple, blue) indicates low amounts.

KEY POINTh The regions most often

involved in traumaticbrain injury includepolar and orbital frontallobes, polar and inferiortemporal lobes, anddorsal frontal andparietal lobes. Lesscommon areas includethe perisylvian regionsand inferior cerebellum.


PET and SPECT


CONCLUSIONNeuromolecular imaging is physiologicimaging of the cerebrum. Both basalphysiologic and specific neurochemicalsystems can be examined. The litera-ture has shown high diagnostic accu-racy in a wide range of disorders,including dementia, brain tumors, epi-lepsy, parkinsonism, cerebrovasculardisease, and TBI. Expanding utility inother disorders will likely be shown inthe future. New radiopharmaceuticalstracing new and different physiologicprocesses are expected.

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PET and SPECT


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inNeurology ComputedTomography Single-PhotonEmission ... · PositronEmission Tomographyand Single-PhotonEmission ComputedTomography inNeurology RobertS.Miletich,MD,PhD,FAAAS ABSTRACT