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SPECT in Neuropsychiatric Diagnosis
Theodore A. Henderson, MD, PhD
Child, Adolescent & General Psychiatrist
President
The Synaptic Space
Co-Founder
Neuro-Luminance Brain Health Centers Inc. 1
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DisclosuresTheodore A. Henderson MD, PhD is President and Chief Medical Officer of The Synaptic Space – a neuroimaging consulting firm
◼ Co-Founder of Neuro-Luminance Brain Health Centers Inc. – a diagnostic and treatment company
◼ Past Officer of the Brain Imaging Council of the Society of Nuclear Medicine (Secretary, Treasurer)
◼ SNMMI Brain Imaging Outreach Working Group
◼ President of the International Society of Applied Neuroimaging
◼ Co-Founder of the Neuro-Laser Foundation
◼ Owner and Principal Dr. Theodore Henderson Inc.
FDA Disclosure
This presentation includes discussion of off-label uses
of medications approved by the FDA2
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Financially Motivated
◼ Two consulting firms concerning neuroimaging
◼ Have no ownership interest in SPECT imaging centers
◼ Refer patients to local independent hospitals for SPECT scans
◼ 3.4% of total gross income directly from SPECT scans
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In Memoriam – Dr. Ismael Mena
Pioneer
Mentor
Gentleman
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Teaching Points
◼ Primates have color vision
◼ SPECT can accurately differentiate TBI from
PTSD
◼ SPECT scans help to reveal co-morbidities and
clinically unrecognized pathology
◼ Mysterious illness
◼ Clear-cut illness
◼ SPECT already meet CED criteria
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Claude Monet 7
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Aspelund et al., J. Exp. Med, V212, pp991-999, 20158
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Normal Transverse Brain SPECT Images
Courtesy Dr. M. Devous9
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Courtesy Simon DeBruin
Good Lion Imaging11
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84%
98%
72%
78%
60%
40%
66%
A
B
12Devous et al, ‘96; Mena et al, ‘99
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15Segami Software15
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“SPECT has emerged as a useful tool for the
evaluation of a variety of neurological
disorders”
◼ - “We must have a systematic way to prepare &
obtain data, display the data we obtain and read
the images” – Waxman
◼ Lack of use of SPECT – “inadequate promotion
by nuclear physicians” – Tikofsky
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“SPECT has emerged as a useful tool for the
evaluation of a variety of neurological
disorders”
◼ - “We must have a systematic way to prepare &
obtain data, display the data we obtain and read
the images” – Waxman
◼ Lack of use of SPECT – “inadequate promotion
by nuclear physicians” – Tikofsky
◼ 1996 – J. Nucl Med 37:14N
TTASAAN Report
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◼ “3-dimension PET systems record a
large fraction of scattered events, such
that the scatter correction is on the
same order as, or even greater than,
that required in SPECT”
◼ An Evidence-Based Review of Quantitative SPECT Imaging
and Potential Clinical Applications – Bailey & Willowson J.
Nucl Med 2013, 54:83-89.
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The Dementias
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B
C D
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◼ Increased PiB binding is found in most AD patients1,2
◼ However, not all AD patients show PiB binding.3,4
◼ Increased PiB binding is found in 61% of patients with MCI.5
◼ Unfortunately, increased PiB binding is found in 12% of 60 year-old normals , 30% of 70 year-old normals & in 50% of 80 year-old normals.4,6
1. Klunk WE et al. Ann Neurol. 2004; 55(3): 306–319
2. Pike KE, et al. Brain.2007; 130(Pt 11): 2837–2844;
3. Cairns NJ, et al. Arch Neurol. 2009; 66(12): 1557–1562;
4. Henderson TA CNS spectrums 2012; 17 (4):176-206.
5. Mintun MA, et al. Neurology. 2006; 67(3): 446–452
6. Rowe CC, et al. Neurology.2007; 68(20): 1718–1725
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◼ Amyloid PET scans face many challenges
◼ Cost of tracer $1,800 USD or greater
◼ Cost of scan $3,000 USD or greater
◼ CMS (Medicare) not reimbursing
◼ Starting at age 65 may be too late
Neurology Today, March 7, 2013 13(5)
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Precision of Diagnostic Modalities for AD vs. NC
◼ Clinical evaluation & neuropsychological testing to autopsy◼ 76-85% sensitivity; 55-70% specificity; 69% positive predictive value1
◼ SPECT with single-headed camera◼ 74-96% sensitivity; 81-84% specificity; 90% positive predictive value2
◼ SPECT with multi-headed camera◼ 82-96% sensitivity; 84-90% specificity; 94% positive predictive value3
◼ FDG PET◼ 86-96% sensitivity; 70-90% specificity; 90% positive predictive value4
◼ 90% sensitivity; 98% specificity in one study (Mosconi et al., JNM 49:390, 2008)
◼ Amyloid markers◼ 86-90% sensitivity, 78-91% specificity dep on age5
1. Lim et al., J Am Geriatr Soc. 47:564, 1999; Knopman et al, Neurology56:1143, 2001.
2. Silverman, J. Nucl Med 45:594, 2004; Dougal et al., Am J Geriatr Psych 12:554, 2004
3. Jobst et al., Int Psychogeriatr 10:271, 1998; Bonte et al., J Nucl Med 45:771, 2004; Matsuda et al., Am J Neurorad 28:731, 2007;
4. Hoffman et al., J Nucl Med 41:1920, 2000; Silverman et al, JAMA, 286:2120, 2001; Patwardham et al., Radiology 231:73, 2004; Bohnen et al., JNM 53:59, 2012
5. Rowe, Alzheimer’s Association Intern. Conf 2010 23
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0 50 100
Sens
Spec
PPV
Amyloid
FDG
SPECT
Clinical
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• 99Tc-HMPAO perfusion SPECT is safe and effective modality to distinguish diagnostic patterns of cerebral perfusion in neurodegenerative dementias and progressive cognitive impairment.
• Sensitivity, specificity, and positive predictive value of SPECT is comparable to FDG-PET and superior to amyloid scan in the elderly.
Conclusions
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Traumatic Brain Injury (TBI)
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SPECT IS WIDELY ACCEPTED FOR
TRAUMATIC BRAIN INJURY
◼ Society of Nuclear Medicine Brain Injury Council-1996
◼ Use of SPECT in the management of patients with moderate to severe head trauma is now well recognized.
◼ Society of Nuclear Medicine-1999 Procedure Guidelines
◼ TBI is a common indication for use of SPECT
◼ European Association of Nuclear Medicine-2002 Procedure Guideline
◼ SPECT has prognostic value. All forms of TBI are considered to be common indications for its use.
◼ Center for Disease Control – 2003 Report to Congress
◼ SPECT has diagnostic use in mild traumatic brain injury.
◼ American College of Radiology-2003 Practice Guideline
◼ Symptomatic TBI, especially in the absence of CT and/or MRI findings is considered to be a clinical indication for use of SPECT.
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◼ Abu-Judeh et al., JALASBIMN, 2(6), 2000
◼ Study of 228 patients with mild to moderate TBI from charts
◼ All had CT or MRI which were read as normal
◼ Read blinded to clinical condition interspersed with 132 controls
who were scanned for other reasons and 30 severe TBI cases
◼ Each case was read twice in the course of study
◼ In patients with no LOC – 68% abnormal SPECT, 32% normal
◼ 46% had frontal lobe hypoperfusion
◼ 55% had basal ganglia/thalamic hypoperfusion
◼ 18% had temporal lobe hypoperfusion
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◼ Shin et al., Brain Injury 20:661, 2006◼ 13 patients with moderate TBI vs. 21 carefully
screened controls
◼ GCS 6.92 + 3.88
◼ MRI and SPECT (ECD) at 2 weeks
◼ MRI negative in 50% of cases; 100% of controls
◼ SPECT positive in 100% of cases; none of controls
◼ Hypoperfusion found in anterior cingulate, frontal lobes, temporal lobes, and parahippocampal gyrus
◼ Statistical parametric analysis relative to control group
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SPECT’s Ability to Track Treatment Results
No. of Months
Post-trauma0 3 6 12
Sensitivity 78% 91% 100% 100%
Specificity 61% 61% 53% 85%
Negative
Predictive Value
92%(3)
100%(12)89% 100% 100%
Positive
Predictive Value44% 64% 52% 83%
Jacobs A, Put E, et al. Prospective Evaluation of Technetium-99m-HMPAO SPECT in Mild and Moderate Traumatic Brain Injury. J
Nucl Med. 1994 Jun; 35(6), pp. 942, 945-946.
Jacobs A, Put E, et al. One-year Follow-up of Technetium-99m-HMPAO SPECT in Mild Head Injury. J Nucl Med. 1996 Oct;37(10), pp.
1605, 1607-1609.
Karonen JO, Ostergaard L, et al. Diffusion and perfusion MR imaging in acute ischemic stroke: a comparison to SPECT. Comput
Methods Programs Biomed. 201Jul;66(1):125-128.
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• bilateral angular gyrus
• anterior and posterior cingulate gyri
• precuneus
• inferior orbital frontal cortex
• superior parietal lobe
• hippocampus
• parahippocampal gyrus34
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A CB
PTSD PTSD + TBITBI
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Diagnostic utility of quantitative brain SPECT
using default mode network
Variable Sensitivity Specificity Accuracy
(95 % CI)
PTSD from TBI
Baseline 92 85 94 (88–99)
PTSD/TBI from TBI
Baseline 85 81 83 (76–90)
PTSD/TBI from PTSD
Baseline 87 83 92 (86–99)
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Incidence and factors regarding
Autism
Incidence: now 1 in 68 (8 year olds) (ASD in 1980 1 in
10,000)
330M x 18% (<19 years)(1:68) = 1 Million kids/young
adults
Why no overt concern?
(at its highest incidence - Polio 1 in 2000)
- No known cause
- Not “terminal” illness, and there is no “cure,”
- Therefore millions of autistic individuals (and their atypical
behavior, and their co-morbidities) will “be with” our children
and grandchildren for the rest of the Century
- Estimated management costs?
$ 1.2 Trillion per 100,000 over next 50 years41
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Brain function information can be used to document:
Co-morbidity = other neurological conditions that frequently occur with autism
and
which add their own element of brain dysfunction to the autism dysfunction:
◼ Seizure – 50+% (non-propagating)
◼ Anxiety◼ post traumatic stress disorder (PTSD)
◼ “Bullying”
◼ Obsessive behavior (repetitive behavior)
◼ Cognitive inflexibility/ADHD
◼ Mood disorder – “depression” or “bipolar”
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“Reframing” the Paradigm about treating
the symptoms of Autism ©
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ADHD – Also not a single entity
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Behavioral Phenotype
• Fidgeting
• Unable to stay seated
• Moving excessively (restlessness)
• Difficulty paying attention
• “On the go”
• Talks excessively
• Blurting out answers
• Loses things/disorganized
• Interrupting/Intruding
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Overlapping Diagnostic Criteria
Restlessness X X X X X
Poor Concentration X X X X X X
Increased motor activity X X X X X
Distractibility X X X X X X
Irritability X X X X
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Diane Purper-Ouakil et al. Pediatric Research
(2011) 69, 69R–76R 53
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Prefrontal Cortex functioning
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The prefrontal cortex increases from green and yellow at Baseline to
brown and red during Test, indicating increased activity while
concentrating.
Sagittal View: Patient at Baseline Sagittal View: Patient during Test
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See frontal lobes go from white, pink, red, and brown at Baseline to yellow and
green during Test below, indicating decreased activity while concentrating.
Sagittal View: Patient during TestSagittal View: Patient at Baseline
• The patient is a 13-year-old female diagnosed by psychiatrist
with Bipolar Disorder
• Primary insomnia, distractibility, elevated mood, irritability,
anxiety, talkativeness, impulsivity
• Failed trials of lithium and valproate.
• Psychiatrist wanted to prescribed quetiapine (Seroquel)
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◼ Lee et al., Human Brain Mapping 24:157,
2005
◼ 40 drug-naïve children with ADHD (9.7 + 2.1 years)
◼ 17 children in comparison group with negative SPECT scans
◼ SPECT scans at start and at 5 weeks of treatment
◼ Dual head camera with parallel coll. (LEHR) analyzed with
SPM99
◼ Methylphenidate 0.7 mg/kg divided BID
◼ Untreated ADHD patients showed hypoperfusion relative to
controls
◼ Medial frontal lobes
◼ Orbital frontal lobes
◼ Cerebellum
◼ Untreated ADHD patients showed increased perfusion of
occipito-parietal cortex 56
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Cherkosova & Hechtman, Can J
Psychiatry 2009, 54:651
◼ Comprehensive review of current neuroimaging literature on ADHD
◼ Reviewed fronto-striatal literature
◼ Emphasized cerebellum◼ ADHD patients made more errors and showed decreased
cerebellar activity with unexpected stimulus timing
◼ Often posterior cerebellar vermis involved overlapping with autism
◼ Emphasized parietal cortex◼ Correlated with decreased working memory, inhibition,
spatial working memory, alertness, and performance monitoring
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Cherkosova & Hechtman, Can J
Psychiatry 2009, 54:651
◼ Emphasized temporal lobe
◼ Perfusion in temporal lobe lower in subjects with
worse impairment from ADHD (Gustafsson, Acta
Paediatr 2000)
◼ Reduced temporal lobe activity during odd-ball task in
ADHD subjects
◼ Reduced temporal lobe activity during response
switching task
◼ Reduced posterior temporal lobe activity during
auditory continuous performance task
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◼ Lorberboym et al., J Child Neurol 19:91, 2004
◼ 19 children with research criteria diagnosis of ADHD (12.0
+ 2.4)
◼ 8 with pure ADHD
◼ 11 with ADHD comorbid for ODD, Conduct d/o, Mood
d/o, or learning d/o
◼ SPECT scans during TOVA
◼ Compared to 9 normal controls (age matched)
◼ Pure ADHD group had frontal lobe hypoperfusion
◼ Comorbid group had frontal and temporal lobe
hypoperfusion
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Binkovitz and
Thacker, 2015;
Current
Psychiatry
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Schneider et al, 2014 J Neuropsychiatry Clin
Neurosci 26(4):335
◼ Specifically examined orbitofrontal cortex
hypoperfusion
◼ Compared to DSM-IV ADHD diagnostic criteria
◼ Conventional tomogram interpretation
◼ Sensitivity 4%, Specificity 97%, PPV 44%
◼ 3-D rendering interpretation of baseline scan
◼ Sensitivity 54%, Specificity 76%, PPV 60%
◼ 3 D rendering interpretation of concentration
scan
◼ Sensitivity 69%, Specificity 84%, PPV 79%
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Raji CA, Willemier K, Tarzwell R, Henderson
TA, Taylor D, Amen DG. Submitted
◼ Adults ADHD patients without comorbidity
N = 340
◼ Adult ADHD patients with comorbidity
N = 7,549
◼ Healthy adult controls N = 116
◼ Largest study ever undertaken by 1 order of
magnitude (2 orders of magnitude if comorbid
patients included)
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◼ Comparing single diagnosis ADHD vs.
Controls
◼ SPECT scan at baseline (rest)
◼ Region of Interest (ROI) analysis
◼ 100 % sensitivity
◼ 100% specificity
◼ 100% accuracy
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• Left calcarine
• Left Heschl
• Bilateral precuneus
• Left supramarginal gyrus
• Left posterior mid-temporal
• Left temporal pole
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◼ Comparing single diagnosis ADHD vs.
Controls
◼ SPECT scan at baseline (rest)
◼ Visual Read
◼ 87% sensitivity
◼ 81% specificity
◼ 92% accuracy
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• genu of anterior cingulate
• Left putamen
•Right occipital cortex
•Right parietal cortex
• Medial anterior prefrontal cortex
• Left prefrontal cortex
• Left posterior temporal
• Left medial temporal
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◼ Comparing single diagnosis ADHD vs.
Controls
◼ SPECT scan on-task (concentration)
◼ Region of Interest
◼ 100% sensitivity
◼ 100% specificity
◼ 100% accuracy
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• Left anterior cingulate
• Left superior orbital frontal cortex
• Left caudate
• Left putamen
• Right Heschl’s gyrus
• Left posterior temporal
• Right temporal pole
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◼ Comparing comorbid ADHD vs. Controls
◼ SPECT scan on-task (concentration)
◼ Region of Interest
◼ 100% sensitivity
◼ 100% specificity
◼ 100% accuracy
◼ Visual Read
◼ 99% sensitivity
◼ 99% specificity
◼ 99% accuracy
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Seeing beyond the group data…
Neurobiological phenotypes presenting with
the behavioral phenotype of ADHD
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Case Example
◼ 7 yr old female
◼ Diagnosed with ADHD, but became wildly out of
control on stimulant medication.
◼ Aggressive on Strattera
◼ Still having lots of problems in school, unable to
sit still, irritable around homework, and impulsive
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Mitigates against ADHD-like processes
69
See prefrontal cortex remain red, pink and white at Baseline and
during Test below.
Sagittal View: Patient at BaselineSagittal View: Patient at Baseline Sagittal View: Patient during Test
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◼ Improved dramatically on oxcarbazepine
(Trileptal) which is a non-toxic metabolite
of carbamazepine (Tegretol).
◼ Grades improved over 6 weeks
◼ Stable for 37 months
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Case Example
◼ 10 yr old female
◼ Evaluated by qEEG and diagnosed with severe
visual and auditory attention problems.
◼ Recommended qEEG Neurofeedback. $10,000
later, no change or benefit.
◼ Evaluated by “Behavioral Optometrist” and
diagnosed with eye tracking problems
◼ Recommended vision therapy
◼ $7,000 later, no difference.
◼ Treated with stimulant – became agitated and
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◼ On interview, she is bright, articulate,
cooperative and inquisitive
◼ Math comprehension at 35%tile
◼ Reading comprehension at 10% tile
◼ Writing at 15%tile
◼ Connor’s Continuous Performance Test –
negative
◼ Paragraph with incomplete sentences,
fragmented ideas and poor penmanship
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◼ Started on Aricept (donepezil) 5 mg qD
◼ 1 month later –
◼ Reading speed has increased
◼ Math skills increased
◼ Writing paragraphs with full sentences and nice
penmanship
◼ 3 months later –
◼ Gained 2 years in math skills
◼ Gained 1.5 years in reading comprehension
◼ Writing stories for fun
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◼ 21 year old female who had always done well in school, achieving A’s and B’s.
◼ Over the past year, she had developed difficulty sustaining attention, distractibility, low energy, severe anxiety, and feeling “sad” and “down”.
◼ Treated with fluoxetine, venlafaxine, and topiramate with little or no benefit.
◼ Her family history included two parents with ADHD and a father with OCD.
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◼ Based on the results of the SPECT scans, the patient was re-assessed by a physician with expertise in chronic fatigue syndrome. The patient was started on a regimen of valacyclovir and amantadine, in addition to her venlafaxine.
◼ Within weeks, she experienced resolution of her symptoms of poor concentration, distractibility, and low energy. 76
Baseline
Concentration
A
BC
D EF
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◼ 43 year old male photojournalist
◼ Over the past three years, he had found it increasingly difficult to manage his schedule, make deadlines, and successfully manage his busy travel schedule.
◼ He was in danger of losing his job due to scheduling errors.
◼ However, he had always done well in school and had not struggled with attention throughout his academic career.
◼ His family physician gave him a trial of Adderall for the presumptive diagnosis of ADHD, but he became irritable.
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ADHD Symptoms from TBI
- fell 20-30 feet off a cliff on location
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SPECT Brain Imaging Already
Meets CED Criteria(Coverage and Evidence Development)
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NOPR – National Oncology PET Registry
◼ Model for PET or SPECT neuroimaging as reimbursable
by CMS (Centers for Medicare and Medicaid Services)
◼ Applied as model for Coverage and Evidence
Development (CED) program for PET amyloid imaging
◼ Criteria
◼ Provide real world data on actual patients
◼ Provide timely data
◼ Utilize large population cohorts
◼ Utilizes modern technology
◼ Shows a benefit
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◼ Provide real world data on actual patients
◼ Tens of thousands of real patients with outcome data from dozens of clinics across US/Canada/Japan/Korea/Etc
◼ Provide timely data
◼ Both retrospective and prospective data
◼ Clinical outcome data with demonstrated scan changes
◼ Utilize large population cohorts
◼ Raji et al, 2015 – 196 Veterans – TBI vs. PTSD
◼ Amen et al 2015 – 20,000 subjects – TBI vs. PTSD
◼ Raji et al, in prep – 8,000 subjects – ADHD
◼ Large control cohorts (hundreds)
◼ Utilizes modern technology
◼ New analysis software; GE software now FDA approved
◼ Shows a benefit
◼ Multiple studies on changes in management and outcome82
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◼ Thornton JF, Schneider H, McLean MK, van Lierop MJ, Tarzwell R. ◼ Improved outcomes using brain SPECT-guided treatment versus
treatment-as-usual in community psychiatric outpatients: a retrospective case-control study.
◼ J Neuropsychiatry Clin Neurosci. 2014 Winter;26(1):51-6.
◼ Amen DG, Jourdain M, Taylor DV, Pigott HE, Willeumier K.◼ Multi-site six month outcome study of complex psychiatric patients
evaluated with addition of brain SPECT imaging.
◼ Adv Mind Body Med. 2013 Spring;27(2):6-16.
◼ Amen DG, Highum D, Licata R, Annibali JA, Somner L, Pigott HE, Taylor DV, Trujillo M, Newberg A, Henderson T, Willeumier K. ◼ Specific ways brain SPECT imaging enhances clinical psychiatric practice.
◼ J Psychoactive Drugs. 2012 Apr-Jun;44(2):96-106.
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SPECT Biomarkers Predicting Treatment
Response ◼ Cho 2007 (N=34) – ADHD children non-responders to
stimulants had higher rCBF in AC and right BG. 88% classified correctly
◼ Amen 2008 (N=157) – Absence of deactivation of PFC in ADHD associated with negative response to stimulants
◼ Navarro 2004 (N=47) – Late onset severe depression, left fronto-cerebelar perfusion ratio PPV = 94% for treatment response
◼ Brockmann 2009 (N=93) – Increased PFC rCBF predicts poor response to SSRI
◼ Langguh 2007 (N=24) – Increased AC rCBF predicts positive response to rTMS
◼ Richieri 2011 (N=18) – Decreased AC rCBF predicts poor response to rTMS
◼ Hanada 2013 (N=45) – decreased rCBF in PFC and AC predicts poor response to SSRI
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SPECT Biomarkers Predicting Treatment
Response
◼ Hoehn-Saric 2001 (N=16) – OCD treatment responders to SSRIs have higher pre-treatment PFC rCBF
◼ Noel 2002 (N=20) – Alcoholics with low PRC rCBF more likely to relapse
◼ Warwick 2006 (N=31) Low insula rCBF predicts positive response to citalopram or moclobemide in social anxiety disorder
◼ Jacobs 1996 (N=136) – abnormal 1 mth SPECT predicts persistent symptoms in mild TBI with 100% sens/85% spec; normal SPECT predicts symptom-free at one year with 100% accuracy
◼ Guedj 2007 (N=17) – fibromyalgia patients with decreased bilat. Medial PFC rCBF predictive of poor response to ketamine with 100% PPV; 91% NPV
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SPECT Biomarkers Predicting Treatment
Response ◼ Bonte 2004 (N=20) – Posterior cingulate rCBF differentiates
Alzheimer’s vs FTD
◼ Bonte 2006 (N=49) – Autopsy-confirmed Alzheimer’s disease based on posterior cingulate perfusion. Sens = 87%; spec 89%.
◼ Jobst 1997 (N=391) – SPECT can predict Alzheimer’s disease with 89% sens; 80% spec
◼ Tanaka 2004 (n=70) – Alz. Dz increased temporal rCBF predicts positive donepezil response
◼ Kanetaka 2008 (N=91) – Alz Dz increased PFC r CBF predicts positive donepezil response
◼ Henderson 2013 – Meta-analysis – SPECT 82-96% sens/84-90% spec. with 94% PPV
◼ Henderson 2013 – Meta-analysis – SPECT for AD vs. FTD –88-90% accuracy with posterior cingulate being key structure
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Demonstrates Treatment Response
◼ NILT response
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◼Criteria◼ Provide real world data on actual patients
◼ Provide timely data
◼ Utilize large population cohorts
◼ Utilizes modern technology
◼ Shows a benefit
◼ Improves treatment outcomes
◼ Predicts treatment response
◼ Reveals unrecognized co-morbidities
◼ Demonstrates treatment response
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Every great
advance in
science has
issued from a
new audacity –
of the
imagination.
John Dewey