Educational Objectives Nuclear • Know what types of PET and SPECT Neurology studies and are clinically available Robert S. Miletich, MD, PhD, FAAAS Professor and Interim Chair • Understand what clinical questions can Department of Nuclear Medicine be addressed SUNY • Decide how to avail Nuclear Neurology: University at Buffalo collaboration or government-mandated [email protected] nuclear training Disclosures: None

Neuroimaging

• Structural • Phrenology - Franz Gall 1796 • Radiography - William Roentgen 1895, Egaz Moniz 1927 Webster • Computed Tomography (CT) - William Oldendorf 1970 Dictionary, • Magnetic Resonance Imaging (MRI) - Damadian 1971 1895 • Functional • Nuclear Brain Scan -1960s & 1970s • Single Photon Emission CT (SPECT) - 1988 • Positron Emission Tomography (PET) - 1997 • CTP, MRP, fMRI - lumen-based imaging

1 Deoxyhemoglobin- paramagnetic

Devlin, 2008 Oxyhemoglobin- diamagnetic

Clinical Brain PET Radiopharmaceuticals FDG • [18F]FDG: Glucose metabolism, universal;  2-deoxy-D-glucose (2DG) is a metabolic poison Neuronal viability; Ischemia-induced increased in high dose; after phosphorylation by anaerobic glycolysis hexokinase, its metabolism stops and it is • Amyloid imaging PET – Available, paid for trapped intracellularly 18 only under CED (research project)  2-[ F]fluoro-2-deoxy-D-glucose (FDG) acts like • [13N]NH3: CBF in 1980s; aNDA 2DG • [11C]Flumazenil: Neuronal viability, NA  with input function and pharmacologic • [15O]H2O: NA modeling quantitation of glucose utilization in physiologic units is possible • [18F]Flurpiridaz: for heart, NA

2 Clinical Brain Nuclear & SPECT Amyloid Imaging, FDA- Radiopharmaceuticals approved, CMS-not approved • Perfusion tracers: [99mTc]exametazine, • CMS: Coverage with Evidence [99mTc]bicisate Development (CED) • [201Tl]Thallous Chloride: Brain tumor • [18F] sensivity & specificity reported in the • [18F]florbetaben 80% range 123 • [18F] • DaTscan, [ I]: DA Transporter • [111In]DTPA: CSF Tracer

Table 1. Characteristics of brain perfusion radiopharmaceuticalsa 99mTc bicisate 99mTc Exametazime 123IIofetamine Common name ECD HMPAO IMP Trade name Neurolite ® CeretecTM SPECTamine ® Tc99m Tc99m I123 Radiochemical stability >6 hrs <30 min Stable Brain perfusion image (41) >24 hrs >24 hrs 1-2 hrs a Extraction fraction (%) (32) 63 47 86

Mechanism of brain retention (26.98) Acid hydrolysis Glutathione Chelation Amine Binding/ Deamination 24-hr whole body retention (%) (26.98) 15 65 70 aOnly data on extraction fraction represent intrasubject comparison. ECD, ethylene cysteinate dimer or bicisate; HMPAO, hexamethylpropyleneamine-oxime; IMP, iodoamphetamine. Nakagawara, et al. JCBFM1994;14(sup1):S49

3 SPECT PET

Diseases Most Common in My PET Nuclear Neurology Practice • Cerebrovascular Disease • Cognitive Impairment, Dementia: neurodegenerative, vascular, psychiatric • Movement Disorders: parkinsonism • CSF-related: NPH, leaks, blocks • Epilepsy • Neuro-Oncology • Traumatic Brain Injury

4 Clinical Goals for Perfusion SPECT

Cerebrovascular  Confirm Diagnosis Disease:  Determine Pathology  Determine Anatomy: Vascular, Large Vessel Disease, parenchymal Small Vessel Disease  Establish Etiology  Identify reversible Ischemia  Establish Prognosis  Guide/Direct Therapy

SPECT Utility in Basis of Perfusion Signal Cerebrovascular Settings  CTP, MRP, fMRI, ASL, U/S are all lumen-based imaging I. TIA  SPECT is cell-based II. Acute Stroke  If there are no cells, there is no III. Subacute/Chronic Stroke SPECT signal IV. Hemorrhage  Bicisate is brain cell specific V. Carotid Disease  Exametazine uptake is in all cells VI. Vertebrobasilar Disease  Micro-infarcts, Selective Neuronal VII. Other Cerebrovascular Settings Loss can be detected by SPECT

5 Cerebral Perfusion SPECT (CPS) Identify Reversible Ischemia Shows 2 phenomena: • Collateral circulation is variable 1. Status of the plumbing, ie. • Ischemia vascular system • Resting: Misery perfusion • Stress: Vascular reserve compromise 2. Neuronal Work, ie. synaptic • Pharmacologic stress activity • acetazolamide (Diamox)  Due to coupling between neuronal • 5-10% CO2 inhalation activity, perfusion and metabolism • Vascular reserve • ability to vasodilate to increase cerebral blood volume • CNS perfusion autoregulation

Elderly male, pre-CABG evaluation, remote H/O transient L body symptoms TIA  Hypoperfusion during and after TIAs  40% still show hypoperfusion one day after TIA Resting Bicisate-SPECT, Symptom Free  Diamox-stress testing increases sensitivity  Increased risk of stroke in hypoperfused territory

6 Elderly male, pre-CABG evaluation, remote H/O transient L body symptoms Elderly male, pre-CABG evaluation, remote H/O transient L body symptoms

Left cerebellum hypoperfusion: Decreased neuronal work or hemodynamic compromise?

Acetazolamide-Stress Bicisate-SPECT, Symptom Free Resting Bicisate-SPECT, Symptom Free

Elderly male, pre-CABG evaluation, remote H/O transient L body symptoms

Left cerebellum hypoperfusion: Decreased neuronal work from diaschisis

Acetazolamide-Stress Bicisate-SPECT, Symptom Free

Luxury Perfusion from Loss of Cerebral Autoregulation

7 Acute Stroke

• Confirm diagnosis: stroke-like presentations • Determine pathology and anatomy • Establish etiology • Identify reversible ischemia • Estimate prognosis • Guide/Direct therapy

MCA WS Brain Diamox Stress Neurolite SPECT

CPS reveals both MCA WS infarcts and resting MCA WS reversible ischemia in both central and peripheral (WS) arterial territory Infarcts

MCA WS

8 Brain Diamox Stress Neurolite SPECT, Post ICA Stent

56 yo M acute L hemiparesis and hemihypesthesia

L R

R anterior choroidal artery Micro-infarcts and Selective Neuronal Loss territory infarct

Carotid Disease

• Identify reversible ischemia 56 yo M acute L hemiparesis and R MCA territory hemihypesthesia reversible resting ischemia • Patient selection for revascularization procedures

R anterior choroidal artery territory infarct

9 64 yo M CAD. Doppler bilateral carotid occlusions 64 yo M CAD. Doppler bilateral carotid occlusions

Resting Neurolite SPECT Diamox-Stress Neurolite SPECT

Unilateral MCA territory resting ischemia or selective neuronal loss? Unilateral MCA territory vascular reserve compromise

57 yo f h/o bilateral distal field PCA infarcts, severe basilar stenosis Vertebrobasilar Disease Rest, Prestent

 Identify reversible ischemia Rt

Rest, Poststent Neurosurg 1999;45:404

10 CPS Insights Hemodynamic Compromise

• Cell-based signal will be more sensitive • Stage 0: Collateral flow paths open to mild flow (and thus perfusion) defects, • Stage 1: Regional Vasodilatation eg. small vessel disease (SVD) PET: CBF OMR CBV • SVD has very high prevalence in population CPS: CBF CVR • Stages of hemodynamic compromise can • Stage 2: Compensation Inadequate be shown with VARCAPS PET: CBF OMR CBV • Cell-based signal signal has high CPS: CBF CVR detectability for selective neuronal loss and neuronal viability (resting ischemia)

Cerebrovascular Reserve Imaging One Day VARCAPS

 Brain stress imaging is pharmacologic. It shows the ability of regional vessels to vasodilate, called vascular reserve. Ischemia causes vessels to  Allows rest and stress imaging in a single scan vasodilate, hence they have little reserve. sesssion which is slightly longer than typical  Stress imaging increases contrast between the  Two injections, two acquisitions, usually both are ½ territories of open vs. stenotic/occluded vessels of typical  Pharmacologic stressor: acetazolamide 1gm IV; 5-  Works on raw stop&shoot scintiphotos 10% CO2 in medical air  Four image sets are generated: rest, stress  Different protocols for this, 1 day VARCAPS or 2 (rest+stress), pure stress, cvri day VARCAPS (Vascular Reserve Cerebral  Pure stress=stress – rest Activation Perfusion Spect)  cvri=pure stress - rest  Neurolite has sufficient counts for either  Ceretec must be 2 day VARCAPS

11 49yoM LICA sacrifice for aneurysm: 2.5 episodic RUE shaking = TIA? Rest Pure Stress 2 L MCA territory A B Vascular reserve compromise 1.5

1 R L

0.5 White matter small vessel disease

0 Bicisate-VARCAPS rest stress pure stress cvri

62yo F with possible TIA = dizzy, tinnitus, face numb: rest SPECT 62yoF dizzy, tinnitus, face numb: Inhaled CO2 gas stress

R R

Frontal hypoperfusion resolved. Dx = Depression

12 Cognitive Impairment, Dementia: Alzheimer's, Other Neurodegenerative, Vascular, Psychiatric

64 yo male 4 year history of progressive cognitive decline M00 (dob //) 0/0-0/0 Cistern FDG-PET/CT

R L

Fig. 2 Alzheimer’s Disease NeurClin 2009;27:61

13 Bicisate-SPECT 73 yo WF with A B memory loss,

Alzheimer’s Disease behavior change and hypothyroid

R L

C D

Frontotemporal Dementia Dementia with Lewy Bodies

Ventral Frontal Hypofrontality of Depression Diagnostic Points • Most dementing illnesses are global brain disorders • Each has its own pattern • There is partial overlap among them • The patterns have diagnostic utility • NMI can distinguish these patterns Orbital and Polar Frontal Hypoperfusion • Amyloid imaging may play an auxiliary role Resting State [Tc-99m]Neurolite-SPECT

14 DEMENTIA Greatest Benefit of NN in Dementia Medial Lt. NDGN > ALZHEIMER Medial Rt. HIGH T DOR.MED.PARIETAL • Memory impairment - early disease LAT.PARIETAL Posterior • Possible (NINCDS-ADRDA) Alzheimer’s dz Anterior LOW T - differential diagnosis LAT.PARIETAL POS.LAT.TEMPORAL VEN.MED.PARIETAL • Mild probable (NINCDS-ADRDA) Lateral Rt. Lateral Lt. Alzheimer’s dz- early disease VERY LOW T MED.TEMPORAL ANT.LAT.TEMPORAL Ventral Dorsal FRONTAL

DEMENTIA DEMENTIA Medial Lt. PSYCH > ALZHEIMER Medial Rt. Medial Lt. VASCULAR > ALZHEIMER Medial Rt. HIGH T HIGH T MED.PARIETAL MED.PARIETAL LAT.PARIETAL LAT.PARIETAL Posterior Anterior Posterior Anterior LOW T LOW T POS.LAT.TEMPORAL LAT.PARIETAL VENTRICLE LAT.TEMPORAL MED.TEMPORAL Lateral Lt. Lateral Lt. Lateral Rt. LAT.FRONTAL Lateral Rt. VERY LOW T MED.TEMPORAL VERY LOW T ANT.TEMPORAL ANT.FRONTAL ANT.FRONTAL Ventral ANT.TEMPORAL Dorsal Ventral Dorsal

Med. Parietal decrease = biomarker of ALZ

15 Red: Deep WM. : Greater SVD Risk

Blue: Superficial WM

Movement Disorders: Parkinson's, Parkinsonism, Ataxia, Dystonia, Dyskinesia

16 Mid 1980s FDG-PET Mid 1980s FDG-PET

FDG-PET screening prior to DBS FDG-PET screening prior to DBS

17 Bicisate-SPECT Bicisate-SPECT

Asymmetric Parkinsonism, Lt>Rt, Psychiatric Patient 73 yoM with tremors, rigidity, festination

Rt DaTscan, ie. [123I]Ioflupane Rt DaTscan, ie. [123I]Ioflupane

Posterior putamen worse anterior putamen worse than caudate Early Parkinson's Disease: Rt. Posterior putamen worst C/W advanced stage idiopathic Parkinson's disease

18 Differential Diagnosis of Parkinsonism A B

 Lewy body disorders: IPD, DLB  Atypical parkinsonian syndromes: MSA, PSP, CBD, FTD (TDP-43) R L  Secondary parkinsonian syndromes: Normal Neurodegenerative Parkinsonism, likely Vascular dz, drugs Parkinson’s Disease  Essential tremor

NMI Benefit in Parkinsonism and Nuclear CSF Study Types Movement Disorders

I. Early Diagnosis  Nuclear Cisternography  CSF Shunt Patency II. Differential Diagnosis  CSF Leak Study III. Therapy Evaluation  CSF Block Study– Chiari malform  CSF Sequestration Study- arachnoid cyst

19 Hydrocephalus, R/O NPH Rt Lateral 48 hour

Anterior 60 yo WM parkinsonism, memory loss

Lt Lateral

Highly Positive for NPH

60 yo WM parkinsonism, memory loss

FDG-PET

20 Nuclear CSF Techniques in Nuclear Cisternography development Interpretation

 QCIS – quantitative cisternography  Ventricular Reflux  CISPECT – cisternography SPECT  Cranial Subarachnoid Distribution  CISRS – CISPECT Registered to Structural images  Clearance  CADCIS – CSF Acute Drainage test with cisternography

77yo Dizzy CISRS at 49 hours 77yo Dizzy CISRS at 49 hours

R L R L

21 82 yo M memory and gait impairment and parkinsonism NN Indications in Epilepsy CPS CISRS

A B I. Localize seizure focus in partial epilepsy II. Lateralize seizure focus in partial epilepsy

R L III. Identify focal vs. multifocal vs. diffuse dz

NN shows at the seizure focus: -hypofunction inter-ictally

Bicisate-SPECT Cisternogram SPECT -hyperfunction ictally registered to MRI

16 yo M with onset of refractory epilepsy at 12 yo

Epilepsy Epilepsy

22 54 yo F epilepsy surgery candidate

A B

FDG-PET Neuro-Oncology: Different Indications, R L C D Tumor Recurrence #1 RESIST: Registered subtraction ictal SPECT

Grading FDG-PET Indications in Gliomas

I. Tumor Grading II. Tumor Staging III. Tumor Localization IV. Differential Diagnosis V. Tumor Recurrence vs. Necrosis VI. Malignant Degeneration VII. Therapy Evaluation VIII. Prognosis

23 Low Grade High Grade

Mass Lesion Differential Mass Lesion Diagnosis Differential Diagnosis

24 Malignant Degeneration Malignant Degeneration

Survival of AA and GBM H/O Lt Occipital GBM 2 yrs.ago, S/P surg, RT, chemo, new CE lesion with low vs high metabolism: FDG-PET IS TELLING US FDG-PET CT PET/CT CE T1WI SOMETHING HISTOLOGY IS NOT

7 mm hypermetabolic nodule C/W recurrence high-grade glioma

25 63 yo M new onset sz 2 months before H/O Rt Frontal mass 4 years ago, low GMR and no CE. Now MRI CE

FDG-PET CT PET/CT CE T1WI FDG-PET CT PET/CT CE T1WI

Sliver of hypermetabolism, C/W malignant degeneration Noncorrespondence of PET and MRI. 10 mm hypermetabolic nodule C/W high-grade glioma

201 [ Tl]Thallous Chloride SPECT [201Tl]Thallous Chloride SPECT Rt Temporal Lobe GBM Rt Temporal Lobe Herpes Encephalitis

26 22 yo M with 1.5 yr H/O mood and cognitive impairment after MVA 70yoM MVA 10 mo ago, memory,

A multitasking problems, 24/30 MMS

B

R L C

Traumatic Brain Injury Traumatic Brain Injury

Requirements for Nuclear Neurology Nuclear Neurology Regulations

• Professional: Training • Nuclear Regulatory Commission (NRC) • Professional: Certification • NRC or States regulate: 37 Agreement States • Professional: Authorized User on RML • RML specifies what radioisotopes & quantities • Center: Staffing, Equipment • To supervise and interpret nuclear studies, you must be an Authorized User (AU) on the • Center: Accreditation from ACR or IAC RML • Center: Radioactive Materials License(RML) • To be AU, you need government-recognized • Center: Insurance Accreditation appropriate training and experience • Business: Payers • Training is in Title 10 Code of Federal • Business: Customers Regulations Subpart 35.290

27 10 CFR 35.290 Board Path 10 CFR 35.290 Attestation Path • Certification by Medical Specialty Board • Preceptor Authorized User attests to: • 700 hours of training and experience in • 700 hours of training and experience in radionuclide handling and safety in medical radionuclide handling and safety in medical use of unsealed byproduct material use of unsealed byproduct material • Pass an exam in radiation safety, • 80 hours of classroom and laboratory radionuclide handling, quality control training • American Board of Nuclear Medicine • Requirements are exactly the same as the • American Board of Radiology Board path • Osteopathic equivalents of 2 above • This path may not be available in all states • Certification Board of Nuclear Cardiology

10 CFR 35.290 Didactic Training 10 CFR 35.290 Work Experience

• 80 hours of classroom and lab training in: • 700 Hours Supervision by an Authorized User: • Handling radioactive materials, surveys • Radiation physics and instrumentation • Quality control of equipment • Radiation protection • Human subject dosages quality control • Mathematics of radioactivity • Administrative controls to prevent medical • Chemistry of byproduct material for events from unsealed byproduct material medical use • Safely contain radioactive material spills and • Radiation biology decontamination • Administering radioactive drugs • Quality control and eluting generators

28 Nuclear Neurology Training

• 2 Year Fellowship • ABNM Board Certification: 2 years training for diplomates of ABPN • ASN can function as clearing house of training • ASN can help establish the Certification Board of Nuclear Neurology

29