Imaging in Dementia:

Imaging in Dementia: Options for Clinical Practice 2017 John A. Bertelson, MD Clinical Chief of Neurology, Seton Brain and Spine Institute Assistant Professor of Medicine, Dell Medical School, UT Austin Clinical Assistant Professor of Psychology, UT Austin

None Disclosures

Outline Early Imaging Indications for Imaging in Dementia Imaging of Alzheimer s Disease Imaging of Other Dementing Disorders Future Directions

Early Dementia Imaging- Pneumoencephalography Initially described in 1918 1 Low resolution High morbidity, including: Meningeal irritation, 6 hrs: Headache Nausea Emesis Elevation in BP Became obsolete in 1971 2 1: AJNR 2012 2: http://www.isradiology.org/tropical_deseases/tmcr/chapter45/imaging.htm

Modern Imaging

Traditional Role for Neuroimaging in Dementia Indication: Rule out reversible process Quality Standards Subcommittee of the AAN, 1994: Neuroimaging should be considered in every patient with dementia potentially treatable disorders that can otherwise be missed, such as tumors, subdural hematomas, hydrocephalus, and strokes. there is no consensus on the need for such studies in the evaluation of patients with the insidious onset of dementia after age 60 without focal signs or symptoms, seizures, or gait disturbances. Alter M, 1994

Evolution of Indications for Neuroimaging in Dementia Entity Year Recommendations AAN 1994 Neuroimaging is not routinely recommended CCCD 1999 Neuroimaging (head CT) is recommended only in select situations AAN 2001 Structural neuroimaging (noncontrast CT or MRI) is appropriate in the routine initial evaluation of patients with dementia Structural imaging is recommended in every patient suspected of dementia: EFNS 2007 - Noncontrast CT can identify surgically treatable lesions and vascular disease. - To increase specificity, MRI should be used. EFNS 2012 Structural imaging (CT or MRI) is recommended in the routine evaluation of every patient with dementia, to exclude secondary causes of dementia. Key: AAN: American Academy of Neurology CCD: Canadian Consensus Conference on Dementia EFNS: European Federation of Neurological Subspecialties From: Bertelson and Ajtai, 2014

Reversible Causes of Dementia Copenhagen Memory Clinic Potentially reversible etiologies for cognitive symptoms In 1000 memory clinic patients 4-5% Hejl A 2002

Neuroimaging in Dementia

Alzheimer s Disease (AD)

Alzheimer s Disease The most common cause of dementia Affects over 5 million Americans 6th leading cause of death for people in the US Affects 1 in 9 age 65 and older, 1 in 3 over age 85 About 10% of people have early onset which affects people under age 65

Histopathologic Hallmarks of AD Major histopathologic hallmarks include Amyloid-β plaques Neurofibrillary tangles Neuronal and synaptic loss AP NFT AP = amyloid plaques. NFT = neurofibrillary tangles. Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation.

Model of the Dynamic Biomarkers of Alzheimer s Disease Sperling RA, 2011

NIA-AA Diagnostic Criteria for Dementia due to Alzheimer s Disease Probable AD dementia w/ evidence of the AD pathophysiological process Possible AD dementia w/ evidence of the AD pathophysiological process Pathophysiologically proved AD dementia Biomarker Biomarker To improve the certainty that the basis of the clinical dementia syndrome is the AD pathophysiological process Dementia unlikely to be due to AD McKhann GM, 2011

AD Imaging Biomarkers Brain Aß amyloidosis PIB/florbetapir-PET Neuronal injury FDG-PET Brain Tau Deposition Tau tracer-pet MRI atrophy Medial temporal lobes Paralimbic Temporoparietal cortex

MRI and AD

Posterior Cortical Atrophy (PCA) Variant of AD Visuospatial impairment Prominent atrophy of parietal and occipital cortex

Automated volumetric MRI analysis Hippocampal Volume Eval. NeuroQuant, CorTechs Labs Inferior Lateral Vent. Commercially available Reported: Volumes of hippocampi (HV) and inferior lateral ventricle (ILV) Hippocampus Volumes as % of intracranial volume Normative %, based on age and gender

Volumetric MRI Analysis- NeuroQuant http://www.cortechs.net/products/neuroquant.php

Volumetric MRI Analysis- NeuroQuant http://www.cortechs.net/products/neuroquant.php

PET and AD FDG PET Amyloid PET Tau PET

FDG PET Medicare Guidelines in Dementia Effective 9/15/2004, An FDG PET scan is considered reasonable and necessary in patients with: a recent diagnosis of dementia, documented cognitive decline of at least 6 months, meet diagnostic criteria for both AD and FTD. http://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/ncd103c1_part4.pdf

FDG PET Medicare Guidelines in Dementia Additional prerequisites include: Comprehensive evaluation already completed, including brain CT or MRI Evaluation by a physician experienced in the diagnosis and assessment of dementia Evaluation is indeterminate and FDG PET is reasonably expected to clarify the diagnosis between FTD and AD SPECT or PET have not already been obtained in the past 12 months AND significant clinical changes have occurred

FDG PET AD FTD PPA

Amyloid PET Imaging Pittsburgh Compound-B PET Pittsburgh Compound-B (PIB) Radiolabeled thioflavin derivative T1W-MRI PIB- PET [N-methyl-(11)C]2-(4 - methylaminophenyl)-6- hydroxybenzothiazole Control Selectively binds to amyloid plaque and cerebrovascular amyloid Significant retention seen in: 90+% AD patients 60% patients with MCI 30% normal elderly AD Very short half life: 20 minutes Mathis J Med Chem 2003;46(13) Applied Neurology, Nov. 2005 (suppl) Mosconi J Alzheimer s Dis 2010

Amyloid-binding Radionucleotides Florbetapir (Amyvid) 1 Marketed in US by Eli Lilly Approved by FDA, not covered by CMS for routine use 2 Half life 110 minutes Additional FDA-approved radionucleotides 3 Florbetaben (Neuraceq, Piramal Imaging) Flutemetamol (Vizamyl, GE Healthcare) 1: Florbetapir, package insert 2: CMS Memo (CAG-00431N) 3: Alzforum, downloaded 8.5.14

Tau vs. Aβ Imaging

Tau vs Aẞ Imaging in Alzheimer s Disease Human postmortem studies have shown that it is the density of NFTs and not of Aẞ insoluble plaques that strongly correlates with neurodegeneration and cognitive deficits 1 PET imaging studies suggest that tau deposition more closely correlates with cognition than Aẞ deposition 2 1. Villemagne 2014 2. Brier et al. 2016

Tau in the Brain Phosphoprotein 6 isoforms Stabilizes microtubules Cytoskeletal support Intracellular transport (organelles, neurotransmitters, etc) Associated with AD, PSP, CBGD, CTE, and several variants of FTD.

Tau PET Tracers Ideal tau PET tracer High affinity for phosphorolated tau and neurofibrillary tangles Weak affinity for tau monomers and amyloid 7+ tau tracers developed (F-18)T807 in phase 2 trials

Tau PET: (F-18) T807 A. Normal Axial Sagittal Coronal B. AD James 2015

Frontotemporal Degeneration (FTD)

Frontotemporal Dementia Subtypes Behavioral variant (bvftd) Language variant (Primary Progressive Aphasia, PPA) Nonfluent/agrammatic Semantic Logopenic Gorno-Tempini 2011

Radiologist Diagnosis of FTD with MRI Review of cases of fronto-temporal dementia with brain MRI General radiologists only considered Pick s disease or bvftd in 10% of cases Neuroradiologists considered these diagnoses in 60% of cases Suarez 2009

Imaging Findings in FTD MRI Early: Normal or focal frontal, insular, or temporal atrophy Late: Progressive focal atrophy (usually bilateral) or generalized atrophy FDG PET Early: Hypometabolism in the frontal or temporal regions Late: Generalized hypometabolism Amyloid PET All stages: No significant binding

Progressive Cognitive Decline T=0 years T=3 years T=8 years

Progressive Cognitive Decline T=0 years T=3 years T=8 years P R I M A R Y P R O G R E S S I V E A P H A S I A

Tau PET Imaging in FTD variant: 18 F-AV-1451 (Tau) PET A-C: 3 patients with MAPT mutation D: normal control Smith and Puschmann, 2016

Tau PET Imaging in FTD variant: Inverse Relationship between Tau and FDG PET FDG PET Tau PET Smith and Puschmann, 2016

Imaging of Other Dementing Disorders

Huntington s Disease From: Bertelson and Ajtai, 2014

Progressive Supranuclear Palsy Atrophic midbrain Normal midbrain Reduced AP midbrain diameter From: Bertelson and Ajtai, 2014

Multiple System Atrophy http://radiopaedia.org/articles/multiple-system-atrophy

Multiple System Atrophy From: Bertelson and Ajtai, 2014

Prion Diseases

scjd A DWI hyperintense caudate and putamen B and C DWI hyperintense cortical ribbon From: Bertelson and Ajtai, 2014

Variant Creutzfeldt-Jakob Disease (vcjd) Hockey stick sign DWI hyperintensity in the bilateral medial thalami and pulvinar From: Bertelson and Ajtai, 2014

What s next?? Wider utilization of neuroimaging biomarkers to: Clarify the diagnosis Alzheimer s Disease vs. Non-Alzheimer s Dementias Monitor response to disease modifying agents Limitations Cost Access to advanced imaging Inadequacy of response to disease modifying agents

Clinical, genetic, and pathological spectrum of misfolded proteins in neurodegenerative disease Villemagne 2015

Thank You

Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Towards defining the preclinical stages of Alzheimer s disease: recommendations from the National Institute on Aging and the Alzheimer s Association workgroup. Alzheimers Dement 2011;7:280-92. References Villemagne, VL et al. Tau imaging: early progress and future directions. Lancet Neurology 14 :1(2015) 114-24. Villemagne VL and Okamura N. In vivo tau imaging: Obstacles and progress. Alzheimer s and Dementia 10(2014) S254-64. James OG et al. PET imaging of tau pathology in Alzheimer s tauopathies. Frontiers in Neurology 6(2015): 1-4.

References Alter, M et al (Quality Standards Subcommittee of the AAN). Practice parameter for diagnosis and evaluation of dementia. Neurology 1994; 44:2203-6. Knopman DS et al. Practice Parameter: diagnosis of dementia (an evidence-based review). Neurology 2001; 56:1143-53. Hejl A et al. Potentially reversible conditions in 1000 consecutive memory clinic patients. J Neuro Neurosurg Psychiatry 2002; 73(4): 390-4. Jack CR Jr, Albert M, Knopman D, McKhann G, Sperling R, Carrillo M, et al. Introduction to the revised criteria for the diagnosis of Alzheimer s disease: National Institute on Aging and the Alzheimer s Association workgroup. Alzheimers Dement 2011;7:257-62.

Kalkonde YV et al. Difference between clinical subspecialties in the outpatient evaluation and treatment of dementia in an academic medical center. Dement Geriatr Cogn Disord 2010; 29:38-36. References McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer s disease: recommendations from the National Institute on Aging and the Alzheimer s Association workgroup. Alzheimers Dement 2011;7:263-69. Albert M, DeKosky ST, Dickson D, Dubois B, Feldman H, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer s disease: report of the National Institute on Aging and the Alzheimer s Association workgroup. Alzheimers Dement 2011;7:270-9.

References Borghesani PR et al. Neuroimaging in the clinical diagnosis of dementia: observations from a memory disorders clinic. Journal of the American Geriatrics Society 2010; 58(8): 1453-8. Heister D et al. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology 2011; 77:1619-28. Dickerson BC et al. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 2011; 76: 1395-402. Dickerson BC et al. MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology 2012; 78: 84-90.

References Petersen RC. New clinical criteria for the Alzheimer s Disease Spectrum. Minnesota Medicine 2012. Price DL et al. Investigation of acoustic noise on 15 MRI scanners from 0.2T to 3T. J Magn Reson Imaging 2001; 13(2):288-93. Li TQ and Wahlund LO. The search for neuroimaging biomarkers of Alzheimer's disease with advanced MRI techniques. Acta Radiologica. 2011; Vol. 52 (2): 211-22. Gorno-Tempini ML et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76:1006-14. Snowden JS et al. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001; 70: 323-32.

References Rabinovici GD, Rosen HJ, etal. Amyloid vs. FDG-PET in the differential diagnosis of AD and FTLD. Neurology 2011; 77:2034-42. Suárez J et al. Characterizing radiology reports in patients with frontotemporal dementia. Neurology 2009; 73(13): 1073-4. Kerholz K et al. Positron emission tomography imaging in dementia. British Journal of Radiology 2007; 80:S160-7. Mosconi L et al. Pre-clinical detection of Alzheimer s disease using FDG-PET with or without amyloid imaging. J Alzheimers Dis. 2010; 20(3): 843-54. Laino C Two radioactive tracers detect amyloid, may aid in AD diagnosis. Neurology Today 2012; 12(10): 16-7.