Nuclear Medicine Imaging in Dementia: A Practical Overview for Hospitalists

Transcription

1 CLINICAL FEATURES Nuclear Medicine Imaging in Dementia: A Practical Overview for Hospitalists Lauren Kay Toney, MS, MD 1 Tim J. McCue, MD, FAAFP 1 Satoshi Minoshima, MD, PhD 2,3 David H. Lewis, MD 1 1 Department of Nuclear Medicine, University of Washington, Seattle, WA; 2 Department of Radiology, University of Washington, Seattle, WA; 3 Neuroimaging and Biotechnology Laboratory, University of Washington, Seattle, WA Correspondence: Lauren Kay Toney, MS, MD, 516 E. Union St., #311, Seattle, WA Tel: Fax: laurenkt@uw.edu Abstract: Dementia is a clinical syndrome with diverse presentation, a challenging differential diagnosis, and time-sensitive therapy. The most common cause of dementia in patients aged 65 years is Alzheimer s disease, which now affects 4 million people in the United States, but is often underrecognized, especially in the inpatient population. The hospitalist may have the opportunity to evaluate a patient s initial presentation of dementia. Addressing the inpatient s dementia symptoms can improve overall care and outcomes, so it is imperative that the hospitalist is abreast of recent developments in the dementia workup. The focus of this article is to overview how nuclear medicine imaging of the brain can aid in this process, with perfusion single-photon emission computed tomography (SPECT) and fludeoxyglucose F ( F-FDG) positron emission tomography (PET) as the 2 most common modalities. Our discussion focuses on Alzheimer s disease, as this the most common etiology of dementia in patients aged 65 years; however, we also touch on the other common neurodegenerative dementias (eg, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia) for completeness. We begin with a summary of the most recent published guidelines for each of these neurodegenerative diseases, and then expand on the role that nuclear imaging plays in each. We provide a basic overview of the principles of these nuclear medicine techniques, and then illustrate findings in perfusion SPECT and F-FDG PET for typical patterns of dementia, with emphasis on evidence regarding diagnostic accuracy of each modality, in comparison with accepted gold standards. Finally, we outline some future research topics within the field of nuclear medicine in dementia, including amyloid plaque imaging and dopamine transporter imaging. Keywords: Alzheimer s disease dementia; SPECT; PET; nuclear; frontotemporal; dementia with Lewy bodies Introduction Dementia is a clinical syndrome with diverse clinical presentations and management options. Because of the numerous reversible and nonreversible (ie, neurodegenerative) etiologies of dementia, the initial workup and diagnosis can be a challenge in the inpatient setting. In the United States, Alzheimer s disease (AD) is the most common cause of dementia in patients aged 65 years, affecting approximately 4 million people. 1 It is estimated that in the next 50 years, the prevalence will quadruple as the US population ages. 2 Other common neurodegenerative causes of dementia include vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson s disease dementia (PDD), and frontotemporal dementia (FTD), with variation by age (Figure 1). Estimates of the prevalence of dementia in the US inpatient population range from 13% to 63%, and the majority of Medicare costs for patients with AD are related to inpatient care. 3 Despite this, identification of dementia among inpatients is low (37% 46%) and the diagnosis is often missed. 4,5 This parallels the underdiagnosis of dementia in the greater population, as 50% of all cases of AD are clinically diagnosed e

2 Toney et al Timely and accurate clinical evaluation of dementia is critical because treatments differ and are generally more effective when started before irreversible progression of disease.7 In some patients with AD, the use of US Food and Drug Administration (FDA)-approved cholinesterase inhibitors can delay cognitive and behavioral progression by 9 to 12 months, and delay the need for institutionalization by an average of months.1,8 Hospitalization for falls, aspiration pneumonitis, or other acute illness may be the first sign of dementia, providing the inpatient physician an opportunity for initial workup. Even if a complete dementia workup is precluded by determination of the immediate goals of care, initial steps may be appropriate. Addressing the older inpatient s entire burden of illness (including functional impairments, such as dementia) rather than focusing on a single-organ disease may improve patient outcomes and reduce adverse events.9 The focus of this article is the role of molecular (ie, functional) imaging modalities, such as perfusion singlephoton emission computed tomography (SPECT) and positron emission tomography (PET), in the hospitalist s workup of dementia. We focus on AD, and therefore discussion of other neurodegenerative dementias is presented in less detail for the purposes of differential diagnosis. The topic is framed within a larger discussion about recent advances in the understanding of neurodegenerative diseases, most notably the use of biomarkers acquired through volumetric magnetic resonance imaging (vmri), cerebrospinal fluid (CSF) analysis, genetic testing, and nuclear imaging. Acknowledging that diagnostic accuracy of traditional clinical criteria for AD is relatively low,10,11 these biomarkers potentially fulfill a need for improved accuracy and expediency in diagnosis.12 The recently revised proposed criteria for the diagnosis of AD reflect this.12 Although the criteria are attractive because they focus on the biology of the disease and place less emphasis on the role of dementia recognition (which can be time consuming to demonstrate), there are several obstacles to their implementation in clinical practice that are worth addressing.13 We begin with a discussion of current recommendations in dementia workup, highlighting the role of molecular imaging. Second, we review the fundamentals of molecular imaging technique. Third, we discuss findings in perfusion SPECT and PET of the major dementia subtypes, including current evidence regarding their diagnostic accuracy. Finally, we discuss exciting future directions for research in molecular imaging of dementia. Current Recommendations Alzheimer s disease is characterized histopathologically by deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles that selectively affect cortical projection neurons (ie, neurons that send their axons to distant locations) within association and limbic areas of the cortex.14 The ensuing damage to cholinergic neurons that subserve memory and attention gives rise to insidious and gradual progression of memory, cognitive, and behavioral deficits.14 Figure 1. The most common causes of dementia by age group. Alzheimer s disease is the most common cause of dementia in individuals aged 65 years. Not depicted is the significant overlap of distinct causes of dementia, most commonly AD and VaD.15 Other 30% Other 14% Huntington s disease 5% AD 34% AD 54% Dementia with Lewy bodies 7% Alcohol-related dementia 10% VaD 16% Frontotemporal dementia 12% VaD % Abbreviations: AD, Alzheimer s disease; VaD, vascular dementia. Adapted with permission from J Neurol Neurosurg Psychiatry

3 Nuclear Medicine Imaging in Dementia As mentioned above, although a complete dementia workup in the inpatient setting may not be possible, effective recognition of dementia is a crucial step toward establishing an etiology. Symptoms to be aware of while obtaining a patient history on admission are listed in Table 1. Although memory impairment often presents as a subjective complaint,12 it is common for the patient to deny, minimize, or lack awareness of symptoms if it is believed that problems of memory and cognition are a part of normal aging.6 Throughout the following discussion, we use the term sensitivity to mean the probability that a test will be positive if disease is present (indicating a test s detectability ), and we use the term specificity to mean the probability that a test will be negative if the disease is absent (reflecting the test s ability to distinguish one disease from another). Test accuracy is high when sensitivity and specificity approach 100%. If dementia is suspected, there are several validated memory impairment screening tools available to confirm the need for further formal testing.6 The Memory Impairment Screen is a 4-minute test in which subjects are given the names of items in 4 different categories (animal, city, vegetable, musical instrument) and asked to recall the item in each category after a short delay. This test has both sensitivity and specificity 90% for identification of AD.6,17 Screening yield is optimized by considering that the greatest risk factor for dementia is age.6 A positive result does not automatically mean that the patient has AD, but it does provide an opportunity for the hospitalist to discuss the need for further memory evaluation.6 A negative screen provides the opportunity to reassure the patient that the memory changes are most likely related to normal aging.6 In any case of suspected dementia, before proceeding to more sophisticated diagnostic techniques, there are several basic elements of a patient history and physical examination that should be addressed, as recommended in the 2001 Report of the Quality Standards Subcommittee of the American Academy of Neurology.11,17 Obtaining detailed medical and social history is important to identify clues about timing and onset of symptoms, and should include information from family or other informants.11 Screening for depression with a validated Table 1. Common Symptoms in Initial Presentation of Dementia That May Require Dementia Evaluation Problematic behaviors (eg, verbal abuse, hoarding, being demanding, outbursts) Impaired cognition (eg, memory, concentration, calculation) Abnormal mental phenomena (eg, emotional liability, depression) Impaired function (eg, cooking, finances, grooming) Disturbances in drives (eg, sleep, sex, appetite) Adapted from Practical Dementia Care. instrument, such as the Geriatric Depression Scale, can identify those individuals with depression and coexistent cognitive impairment, a pair highly predictive of underlying dementia.13 In fact, depression alone in the elderly confers twice the risk of becoming demented.19 A careful inventory of medications and substance abuse can help to determine whether there may be pharmacologic contributors to symptoms.19 Because vitamin B12 deficiency and hypothyroidism are comorbidities commonly seen in elderly patients with suspected dementia, laboratory testing in these areas is recommended.11 Routine screening for syphilis, human immunodeficiency virus, or toxic metals is not recommended unless there is particular cause for suspicion.11 The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)-Alzheimer s Disease and Related Disorders Association, Inc. (ADRDA) Alzheimer s Criteria, first proposed in 1984 by the NINCDS (now known as the National Institute of Neurological Disorders and Stroke [NINDS]) and the ADRDA (now known as the Alzheimer s Association), provide a uniform basis for diagnosis through a 2-step process.10 First, a patient must meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for dementia, which require an episodic memory disorder and impairment in ⱖ 1 other cognitive domain, both of which interfere with social function or activities of daily living.10 At that time, a diagnosis of probable AD may be made based on clinical symptomatology.10 These criteria have been validated and remain widely accepted in both clinical and research domains.12,13 However, unless histopathology is available, the diagnosis is probabilistic at best, and is often a diagnosis of exclusion.12 Furthermore, despite an acceptable ability to detect AD (sensitivity estimates, 65% 96%), their ability to distinguish AD from other dementias is poor (specificity estimates, 23% 88%).11,12 This concern about diagnostic accuracy, in addition to advances in biomarkers that can identify AD (in some cases even when dementia is not overtly present) and the recognition that eventual success of disease-modifying drugs demands early disease detection, while neurodegeneration is minimal,12,20 have prompted a landmark update of these criteria.6 The revised NINCDSADRDA criteria for diagnosis of AD were proposed in 2007 (Figure 2).12 In addition to requiring an insidious and progressive impairment of episodic memory, the criteria stipulate supporting evidence from ⱖ 1 biological footprint of the disease, either by structural imaging, CSF analysis, molecular imaging, or genetic testing.12 The proposed framework is not widely used in practice, and it is discussed most recently in a position paper dated 151

4 Toney et al April 2011 by the National Institute on Aging Alzheimer s Association workgroups, which may be accessed on the National Institute on Aging Web site. However, there is great potential for enhanced AD diagnosis, monitoring progression of disease, as well as use in clinical research if the revised NINCDS-ADRDA criteria can be validated through studies comparing it with the current standard.13 Core Diagnostic Criteria for Alzheimer s Disease Diagnosis Mild cognitive impairment (MCI) refers to impairment in ⱖ 1 cognitive domain (eg, memory or executive function) of insufficient severity to cause functional impairment.21 When memory is one of the involved domains, the risk of developing AD is increased; as many as 40% of patients progress to AD over the next 4 years.19,21,22 Single-domain amnestic MCI (amci) refers to patients with impairment limited to the memory domain and is thought to be the earliest clinically detectable stage of AD.21 Amnestic MCI is also a strong harbinger of eventual progression to AD.12,23 Note, however, that use of these and other terms for various stages of cognitive impairment is inconsistent in the literature.13 With this in mind, a diagnosis of AD requires that a deficit appear in episodic memory testing results (eg, recall deficit Figure 2. Proposed 2007 NINCDS-ADRDA diagnostic criteria for diagnosis of Alzheimer s disease. Diagnosis of probable Alzheimer s disease requires core diagnostic criteria, plus ⱖ 1 supportive feature. Core Diagnostic Criteria Presence of an early and significant episodic memory impairment that includes the following features: Gradual and progressive change in memory over a period of 6 months Objective evidence of significantly impaired episodic memory on testing Episodic memory impairment can be isolated or associated with other cognitive changes Supportive Features 1. Presence of medial temporal lobe atrophy on qualitative or volumetric MRI 2. Abnormal cerebrospinal fluid biomarker concentrations, including: - Low Aβ - Increased ttau - Increased ptau 3. Specific pattern on molecular neuroimaging with F-FDG PET - Hypometabolism in bilateral temporoparietal regions - Ligand-specific binding studies (such as amyloid imaging) 4. Proven Alzheimer s diease autosomal dominant mutation within the immediate family Exclusion Criteria Presence of other viable etiology Definitive Diagnosis of Alzheimer s Disease May be made by either histopathologic diagnosis or demonstration of a causative genetic mutation Abbreviations: F-FDG, fludeoxyglucose F ; Aβ, amyloid β; ADRDA, Alzheimer s Disease and Related Disorders Association, Inc.; NINCDS, National Institute of Neurological and Communicative Disorders and Stroke; MRI, magnetic resonance imaging; PET, positron emission tomography; ttau, total tau; ptau, phosphorylated tau. Adapted with permission from Lancet Neurol that does not improve with cueing).12 Tests of delayed recall can discriminate patients with AD from healthy controls with sensitivity and specificity 90%, and discriminate patients with MCI from healthy controls with sensitivity and specificity 80%.12 The deficit must be gradual and progressive over a period ⱖ 6 months.12 Although the memory deficit may be accompanied by other cognitive deficits, demonstration of an additional cognitive deficit (as is required in the DSM-IV diagnosis of dementia) has been abandoned as a requirement in the revised criteria.12 Supportive Features The first supportive feature in the revised NINCDSADRDA criteria for probable AD diagnosis is atrophy of medial temporal lobe structures on vmri, sometimes called quantitative MRI. It is well reported that vmri can be used to visualize the cortical atrophy (seen earliest and most prominently in the hippocampus) that is present in AD and predictive of clinical decline in MCI.21,24 Methods to quantify cortical volume loss have been attempted with visual rating scales (which are only semiquantitative), manual specification of a region of interest, such as the hippocampus (which can be labor intensive), and the use of generic templates to automate region-of-interest drawing (which are subject to error).21,25 A large, prospective, head-to-head comparison of fludeoxyglucose F (F-FDG) PET with vmri overcame these limitations by using software that accurately automates drawing of regions of interest.21 In patients with AD, MCI, and amci, the decline in volume on vmri (most pronounced in hippocampus) was greater than the decline in metabolism on F-FDG PET (most pronounced in entorhinal cortex).26 This suggests that vmri is as sensitive as (if not more than) F-FDG PET in the early detection of AD, which directly challenges the findings of several prior smaller studies.26 Another recent study of the temporal relationship between brain atrophy and hypometabolism in AD analyzed sequential vmri and F-FDG PET studies in patients with amci.24 Findings suggested that hippocampal atrophy occurs first, leading to disruption of fibers that terminate in frontal and cingulate cortices, which, in turn, results in cortical hypometabolism observed on F-FDG PET.24 In other words, structural changes detectable with MRI may precede metabolic changes detectable with F-FDG PET.24 Of note, earlier calculations may overestimate the accuracy of hippocampal vmri in the detection of AD, as they are derived from studies comparing patients with AD

5 Nuclear Medicine Imaging in Dementia with healthy controls.25 A more clinically meaningful metric of accuracy would require a study with a diverse comparison group that includes patients with other causes of memory impairment; such studies have not yet been conducted.25 Therefore, hippocampal vmri will likely continue to require correlation with other clinical features until further work in this area is completed.25 Given the relative expense and limited availability of F-FDG PET, as well as the need for an injection of ionizing radiotracer, the above findings make vmri a promising technique in detection of early AD.21,25 Although vmri is not the standard in most clinical practices, its implementation is being encouraged by further validation studies, as well as current attempts to improve its automation and standardization across centers.25 The second supportive feature for probable AD diagnosis is low amyloid β (Aβ) concentrations, increased total tau (ttau) concentrations, and increased phosphorylated tau (ptau).12 Under the 1984 NINCDS-ADRDA criteria, CSF analysis served primarily as an exclusionary tool to rule out other dementing conditions, such as inflammation, vasculitis, or demyelination. In contrast, these CSF biomarkers potentially reflect primary disease biology in AD.12 Values typically used for this determination are Aβ 500 pg/ml, ttau 500 pg/ml, and ptau 80 pg/ml.27 These markers may identify AD prior to the onset of dementia, and they can predict progression from MCI to AD.28 One study estimates that low Aβ and high ttau concentrations in patients with MCI predict a 17-fold increase in likelihood of progression to AD over a follow-up period of 4 to 6 years.29 These findings underscore the fact that AD pathology is present a number of years before dementia manifests.28,29 However, CSF biomarkers are not currently widely clinically adopted.30 There is significant heterogeneity in measured levels of these biomarkers when obtained from different laboratories, each with their own enzyme-linked immunosorbent assay techniques.31 A recent workshop that was convened to troubleshoot this heterogeneity identified a lack of standardization in multiple laboratory processes (such as pipetting and incubation).32 Although the resulting variation in measured levels of the CSF biomarkers was generally 10%, these differences are still potential sources of clinical error, especially if a discrete cutoff value is used to inform decisions about patient management.32 Compounding this, some individuals have abnormal biomarker values but no AD, which may hamper its clinical utility.30 Cerebrospinal fluid Aβ concentrations are typically normal in patients with depression but decreased in patients with AD, DLB, FTD, and VaD.30 Cerebrospinal fluid ttau concentrations are also normal in patients with depression, but may be slightly raised in patients with DLB and FTD, and markedly elevated in patients with Creutzfeldt Jakob disease.30 In light of the suboptimal assay reproducibility and limited specificity against other dementias, there is a current movement to refine and standardize laboratory techniques, which may soon permit these biomarkers to have a more secure role in the accepted workup of AD.30,32 The third supportive feature is a pattern of bilateral temporoparietal hypometabolism on F-FDG PET imaging. Of note, computed tomography (CT) scan is absent from the supportive features. Although a CT scan may identify brain atrophy, vascular changes, tumor, or acute surgical causes of altered mental status, it has the potential to misguide the workup of dementia.1 In this setting, structural and/or reversible pathology is only identified approximately 5% of the time.1 Furthermore, it can lead to frequent misdiagnosis; one multicenter study demonstrated that after a CT scan or MRI diagnosis of VaD, 55% of patients had AD on histopathology and < 30% actually had isolated VaD.1 The fourth supportive feature is the identification of a familial genetic mutation (ie, amyloid precursor protein, presenilin 1, or presenilin 2). These single-gene autosomal dominant mutations are rare and account for only 0.5% of AD cases.19 Such a mutation confers a definitive diagnosis of AD. Note that these rare gene mutations differ from the common genetic allele, the ε4 allele of apolipoprotein E4 (APOE4), which is carried by half of all demented patients.19 APOE4 is a major susceptibility factor for late-onset AD.27 It is believed to play a role in the pathologic Aβ deposition, as evidenced by observation of a gene dose effect, in which the abnormal increase in cortical Aβ binding is greater in patients possessing 2 ε4 alleles than in patients with 1 ε4 allele.27 This risk is determined by the interaction of APOE4 with other isoforms of APOE, such as APOE3 (conferring a neutral effect) and APOE2 (conferring a protective effect).27 These interactions were confirmed in a recent study with cerebral amyloid imaging and direct measures of CSF Aβ concentration, shedding significant light on the pathogenesis of the disease.27 The revised NINCDS-ADRDA criteria propose a more specific diagnosis of AD by requiring the presence of a biomarker (eg, atrophy on vmri, characteristic patterns on perfusion SPECT or F-FDG PET, abnormal CSF biomarkers, or a familial genetic mutation) in addition to an episodic memory deficit.19 Although this framework requires validation before routine use in clinical practice, 153

6 Toney et al the principles presented are stimulating discussion regarding their implementation and potential to make AD diagnosis more robust.13 Other Causes of Dementia Vascular dementia is clinically characterized by its sudden onset, stepwise progression, and associated risk factors.15 Cognitive dysfunction may result from large-vessel infarcts, watershed infarcts, or small-vessel disease.15 Given the considerable overlap of VaD and AD, with the obvious challenges in diagnosis, the NINDS and Association Internationale pour la Recherché et l Enseignement en Neurosciences (AIREN) International Work Group released criteria for diagnosis of VaD in Molecular imaging is not an explicit component of these criteria.15 Parkinson s disease dementia refers to dementia that often occurs in the setting of well-established Parkinson s disease, which has an onset of usually ⱖ 10 years after motor dysfunction.7 Dementia with Lewy bodies refers to dementia that occurs before or concurrent with the onset of motor parkinsonism (usually by ⱖ 1 year).7 Both dementias are characterized by pronounced fluctuations in attention and cognition, as well as prominent visual hallucinations, making them clinically indistinguishable.7,12 Progressive supranuclear palsy and multiple-system atrophy are much less common atypical parkinsonian syndromes that can manifest as dementia.7 Both DLB and PDD are characterized by pathologic deposition of Lewy bodies and amyloid plaques. Lewy bodies result from abnormal α-synuclein metabolism, and are responsible for damage to the substantial nigra of the brainstem in Parkinson s disease.33 The pattern of Lewy body deposition in DLB and PDD (in the brainstem, basal forebrain, and neocortices) makes these diseases indistinguishable at the pathologic level.7,33 Furthermore, the clinical overlap of DLB, PDD, and AD is confounded by the presence of amyloid deposition. Diagnosis of DLB is made based on the 2005 revised criteria of the third report of the DLB Consortium (Figure 3), in which dopamine transporter imaging, perfusion SPECT, and F-FDG PET play a role.7 Frontotemporal dementia, sometimes referred to as frontotemporal lobar degeneration, is best understood as an umbrella term grouping several neurodegenerative diseases that affect the frontal and temporal lobes, including Pick s disease.34 Frontotemporal dementia is clinically characterized by behavioral changes, disinhibition, and language decline that may precede or overshadow memory symptoms.34 The associated frontal and temporal atrophy is, in many cases, 154 strikingly asymmetric.34 Recent advances in the genetic and biochemical basis of this disease, including the discovery that TDP-43 proteinopathy is present in most sporadic and genetic forms of FTD, have been featured in the 2007 consensus of the Consortium for Frontotemporal Lobar Degeneration for neuropathologic (ie, postmortem) diagnosis of FTD.34 Although these criteria form the basis for the gold standard of diagnosis in FTD, the clinical diagnosis may be aided by molecular imaging.34 Molecular Imaging Techniques in Dementia Perfusion Single-Photon Emission Computed Tomography Perfusion SPECT is a molecular imaging technique in which photons emitted from an injected radioactive tracer (ie, radiotracer) are imaged by rotating camera heads, similar to the technique of CT scan, except that the radiation source is internal to the patient. Brain perfusion SPECT (ie, perfusion SPECT) involves specific radiotracers that depict regional cerebral blood flow (rcbf). Based on the principle that rcbf and metabolism are coupled, perfusion SPECT images can be interpreted to reflect regional neuronal activity. 35 Two virtually interchangeable radiotracers used for this purpose are technetium 99m (Tc 99m) exametazime (Ceretec ; GE Healthcare, Buckinghamshire, United Kingdom) and Tc 99m ethylcysteinate dimer (Neurolite ; GE Healthcare, Buckinghamshire, United Kingdom). These radiotracers are highly lipophilic and easily cross the blood-brain bar- Figure 3. Revised criteria for the clinical diagnosis of dementia with Lewy bodies according to the third report of the Dementia with Lewy Bodies Consortium. Diagnosis Requires - 2 core features or - 1 core feature plus 1 suggestive feature Core Features Fluctuating cognition Recurrent visual hallucinations Parkinsonism Suggestive Features REM sleep behavior disorder Severe neuroleptic sensitivity Low dopamine activity in basal ganglia on dopamine transporter SPECT or PET Supportive Features (add no diagnostic specificity) Severe autonomic dysfunction Depression Generalized low uptake on perfusion SPECT or F-FDG PET with relatively reduced occipital activity Abbreviations: F-FDG, fludeoxyglucose F ; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography. Adapted with permission from Neurology.7

7 Nuclear Medicine Imaging in Dementia rier, where they undergo rapid cellular localization by diffusion. They are then fixed intracellularly. Tc 99m decays by gamma ray emission, and imaging of these photons provides a snapshot of rcbf at the time of injection. Because of the relatively long half-life of the radiotracer (6 hours), imaging can be delayed after the injection, if needed. Sedating agents can be administered after the injection without compromising the images. The primary disadvantage of perfusion SPECT is that its intrinsic spatial resolution is inferior in comparison with F-FDG PET imaging.1 On the other hand, perfusion SPECT is relatively simple to perform and requires an inexpensive and stable isotope, which is widely available. available software packages, such as software for 3-dimensional stereotactic surface projection (3D-SSP), which stereotactically maps the patient s brain to an age-matched standard brain (obtained from population age matched controls). This map enables a comparison of radiotracer uptake at each voxel (3D pixel) in the patient s image with the corresponding voxel in the standard brain, yielding a numerical z-score that quantifies this comparison. A map of color-coded z-scores allows subtle regional abnormalities to be appreciated.37 Molecular Imaging Findings in Alzheimer s Disease The PET imaging technique was developed in the 1970s primarily for brain imaging research. In 1998, the Centers for Medicare and Medicaid Services approved F-FDG PET for use in specific clinical applications, such as primary pulmonary tumor staging.36 The use and availability of F-FDG PET has grown with its utility in oncology imaging.36 In 2004, the Centers for Medicare and Medicaid Services approved F-FDG PET imaging for the evaluation of both FTD and AD.36 The most common radiotracer in clinical PET imaging is F. F crosses the blood-brain barrier through a glucose transporter and is transported into the cells by another glucose transport protein, glucose transporter 1. Inside the cell, F and glucose are substrates for hexokinase, undergoing phosphorylation. Unlike glucose, F cannot continue down the glucose pathway and is subsequently trapped within the cell. PET radioisotopes, such as F, decay by positron emission, in which a positron (ie, anti-electron) annihilates with a nearby electron, producing a pair of gamma photons emitted in opposite directions along a line in space. A PET scanner detects these photons in coincidence, which provides radiation event localization information, and, ultimately, higher spatial resolution as compared with perfusion SPECT.1 Comparative studies suggest a 15% to 20% increase in accuracy of PET compared with perfusion SPECT owing to this difference in intrinsic spatial resolution.1 This advantage may be particularly relevant to identification of early-stage disease.1 F-FDG PET and perfusion SPECT images are interpreted visually but are aided greatly by quantitative (ie, use of a computed numerical value representing local radiotracer uptake) or semiquantitative techniques (ie, visual comparison of local radiotracer uptake with that of a relatively unaffected structure, such as cerebellum).33 In addition, there are widely In AD, perfusion SPECT demonstrates decreased rcbf in a typical pattern of bilateral involvement of temporoparietal association cortices with characteristic sparing of the primary sensorimotor cortex, primary visual cortex, and basal ganglia (Figure 4A).1,2,38 Association cortices function in the assembly of auditory, visual, and somatosensory information; many projection neurons synapse in association cortices. Damage to projection neurons may account for the decreased perfusion in their post-synaptic cortical areas.20 The temporoparietal cortices are usually affected in an asymmetric fashion; left hypoperfusion corresponds with diminished language function, and right hypoperfusion corresponds with diminished visuospatial function.39 Other regions involved more variably are the frontal cortex and posterior cingulate gyrus.40 In general, the degree of perfusion abnormality correlates with the degree of cognitive impairment.22 In a large prospective study, perfusion SPECT was able to distinguish patients with AD from healthy controls with high sensitivity (89%) and specificity (80%).39 Furthermore, a recent meta-analysis showed that perfusion SPECT distinguishes AD from other dementias with sensitivity and specificity of 70% to 79% for AD versus FTD and for AD versus VaD.41 In this respect, the standard clinical evaluation of AD is likely more sensitive, while perfusion SPECT is more specific, suggesting that perfusion SPECT has maximal utility in the case of a challenging differential diagnosis.11,12 In one study from a memory disorder clinic at our institution, patients underwent clinical evaluation for dementia, then had MRI and perfusion SPECT performed. In 39% of the cases, the clinical diagnosis was confirmed by imaging (MRI plus perfusion SPECT), in % the differential diagnosis was narrowed (eg, VaD was eliminated), in 24% a new diagnosis was proposed, and in 19% imaging was abnormal or nondiagnostic. In other words, the imaging provided new information in 80% of the cases Positron Emission Tomography

8 Toney et al Two small retrospective studies of MCI suggest that hypoperfusion in parietal and temporal lobes on perfusion SPECT may occur very early in AD; however, these findings should be replicated in larger studies.43,44 Augmenting perfusion SPECT image interpretation with the use of 3D-SSP software has been shown to improve accuracy (sensitivity of 90% vs 61%; specificity was the same).45 The largest difference was seen in cases of mild dementia, with the implication that perfusion SPECT with 3D-SSP may have a unique role in early AD detection.45 F-FDG PET abnormalities are well established in AD, with hypometabolism in bilateral temporoparietal lobes and relative preservation of primary cortices, basal ganglia, and cerebellum (the same regions affected on perfusion SPECT) (Figure 4B). Several meta-analyses confirmed the high diagnostic accuracy of F-FDG PET in AD, with sensitivity as high as 93% and specificity as high as 80%.46,47 It has even been suggested that F-FDG PET is more reliable than clinical diagnosis when evaluating patients with autopsy-confirmed AD.1,48,49 In a side-by-side comparison, F-FDG PET had a diagnostic accuracy approximately 15% to 20% greater than that of perfusion SPECT in early-stage AD.3 As with perfusion SPECT, the accuracy of diagnosing AD is even greater when F-FDG PET image interpretation is augmented with the use of 3D-SSP.37 Dementia with Lewy Bodies In DLB, deposition of Lewy bodies and amyloid is a characteristic histological feature, and loss of dopaminergic neurons Figure 4A. Perfusion SPECT imaging in a patient with Alzheimer s disease demonstrating hypoperfusion in the bilateral temporoparietal cortices and in the posterior cingulate cortex. Abbreviation: SPECT, single-photon emission computed tomography. 156 in the nigrostriatal pathway (including substantia nigra) leads to motor symptoms. The loss of cholinergic neurons in the basal forebrain (including basal nucleus of Meynert) and cortex is thought to account for degrading memory and cognition, as in AD.33,50 Decreased occipital activity on perfusion SPECT and F-FDG PET is the primary finding on molecular imaging in DLB (Figures 5A, B).51 Like patients with AD, these patients often demonstrate a mild perfusion deficit in the temporoparietal and frontal regions, but, unlike AD, DLB usually spares medial temporal lobes.33 Overall, the identification of decreased occipital perfusion is most reliable in separating DLB from AD with both a sensitivity and specificity of 92%.33 Surprisingly, researchers have found that the occipital lobe is least affected by the pathologic deposition of Lewy bodies the hallmark of DLB.33 This poses an apparent discordance between pathology and findings on perfusion SPECT.33 Attempting to resolve this, researchers have studied cholinergic changes with a radiotracer that has an acetylcholine receptor ligand, followed by perfusion SPECT imaging.50 With this technique, patients with DLB demonstrated abnormally reduced uptake in several regions (frontal, striatal, temporal, and cingulate) but increased uptake in occipital lobes.50 This finding was most pronounced in the subset of patients with DLB experiencing visual hallucinations, thereby potentially linking cholinergic changes with symptomatology.50 Although this discovery is interesting, Figure 4B. F-FDG PET imaging in a patient with Alzheimer s disease, with selected transaxial slices (top) and lateral 3D-SSP surface maps (bottom). Transaxial slices demonstrate hypometabolism in the temporoparietal association cortices. Primary sensorimotor and visual cortices are relatively preserved. 3D-SSP maps make these abnormalities more appreciable. Abbreviations: F-FDG, fludeoxyglucose F ; 3D-SSP, 3-dimensional stereotactic surface projection; PET, positron emission tomography.

9 Nuclear Medicine Imaging in Dementia the reason for abnormally decreased occipital perfusion on SPECT, despite relatively low levels of Lewy bodies, remains unclear.50 In F-FDG PET imaging of DLB, the typical pattern is hypometabolism in the temporo-parieto-occipital association cortices and cerebellar hemispheres.52 Clinical differentiation between DLB and AD is a challenge, and it has been shown that F-FDG PET can make this distinction more accurately than clinical evaluation.53 Molecular imaging of the dopamine transporter (DAT) can demonstrate the integrity of the presynaptic neuron terminals in the nigrostriatal pathway.7 Several radiotracers that act as a presynaptic DAT ligands have been developed for this purpose, including Ioflupane 123 ([123I]-FP-CIT) (DaTSCAN ; GE Healthcare, Buckinghamshire, United Kingdom) and Tc 99m TRODAT-1 (GMS Pharmaceutical Co., Ltd., Shanghai, China), intended for use with perfusion SPECT imaging. As might be expected, DAT perfusion SPECT imaging, which provides a snapshot of dopamine activity, is abnormal in idiopathic Parkinson s disease. It is notable that DAT perfusion SPECT imaging is normal in AD, making it a potentially useful tool to distinguish between these diseases (Figure 6).7,54 lobe is more prominently affected. In general, the pattern of hypoperfusion in perfusion SPECT can reliably differentiate FTD from AD.55 F-FDG PET images of patients with FTD have a similar pattern of abnormality; that is, frontotemporal hypometabolism with relative sparing of the motor cortex, caudate, insula, and thalamus.56 The hemispheric asymmetry of hypometabolism (more frequently lateralized to the left) is common in patients with FTD, which may be another imaging feature contributing to its reliability in differentiating FTD from AD.26 Future Directions for Nuclear Imaging in Dementia Dopamine Transporter DAT perfusion SPECT imaging can fulfill a suggestive feature in diagnosis of DLB according to the third report of the DLB Consortium (Figure 3).7 Tc 99m TRODAT-1 is not available for clinical use in the United States.57 DaTSCAN has been available in Europe since 2000, where it is indicated for diagnosing clinically uncertain Parkinson s disease as well as differentiating essential tremor from parkinsonian syndromes. On January 20, 2011, the FDA gave long-awaited approval for the clinical use of DaTSCAN in the United Frontotemporal Dementia Perfusion SPECT imaging in FTD demonstrates perfusion deficits of the frontal and temporal lobes, with relative sparing of the motor cortex, caudate, insula, and thalamus (Figure 7). In one form of FTD, known as Pick s disease, the frontal lobe is affected more than the temporal lobe, and in another type of FTD, known as semantic dementia, in which language disturbance is prominent, the temporal Figure 5B. F-FDG PET imaging in a patient with dementia with Lewy bodies with selected transaxial slices (top) and lateral 3D-SSP surface maps (bottom). The transaxial slices show diffuse cortical hypometabolism, especially in the occipital lobe. 3D-SSP maps make these abnormalities more appreciable. Figure 5A. Perfusion SPECT imaging in 3 axial sections in a patient with dementia with Lewy bodies demonstrates diffuse cortical hypoperfusion, most pronounced in the occipital cortex. Abbreviation: SPECT, single-photon emission computed tomography. Abbreviations: F-FDG, fludeoxyglucose F ; 3D-SSP, 3-dimensional stereotactic surface projection; PET, positron emission tomography. 157

10 Toney et al States after a delay as a result of the fact that the active component of the DaTSCAN radiotracer is a cocaine analog. Positron Emission Tomography Amyloid Imaging Although the etiology of AD has not been established, evidence strongly suggests a causative role of Aβ in the pathogenesis.58 Based on the well-accepted neuropathological criteria for diagnosis of AD, which include deposition of Aβ, a test of Aβ burden in subjects with cognitive impairment could potentially rule out the disease.59 Furthermore, as Aβ is currently under investigation as a potentially modifiable target for neurorestorative therapy (others include α-, β-, and gamma-secretase modulators, tau kinase inhibitors, nerve growth factors, and insulin), such a test could provide an objective measure of AD pathology that is useful in evaluating the effectiveness of these therapies.59 The first breakthrough in amyloid imaging in 2004 was a proof-of-concept study using a radiotracer called Pittsburgh compound B (PiB).60 Pittsburgh compound B aggregated in association cortices of patients with AD in a pattern consistent with that demonstrated in postmortem studies of the AD brain.60 Namely, PiB was retained in the frontal, temporal, and parietal association cortices in patients with AD, but not in healthy controls.60 The limited clinical utility of PiB due to the short 20-minute half-life of the radioisotope Carbon 11 has Figure 6. Perfusion SPECT dopamine transporter imaging in A) a healthy control, B) a patient with Parkinson s disease, C) a patient with Alzheimer s disease, and D) a patient with dementia with Lewy bodies. Note normal radiotracer uptake in basal ganglia of the healthy control and the patient with Alzheimer s disease, but decreased uptake in basal ganglia of the patients with Parkinson s disease and dementia with Lewy bodies. been overcome with development of other amyloid-binding radiotracers containing F (eg, F-FDG).58,61 Phase 1 and 2 trials have demonstrated the safety of 2 such compounds, F-AV-45 (florbetapir)58 and F-BAY Both radiotracers demonstrated a pattern of retention similar to that demonstrated with PiB and reliably differentiated AD from healthy controls with visual inspection of PET images.58,61 In perhaps one of the most significant advances in AD research, a recent report from an ongoing phase 3 clinical trial with florbetapir (believed to have favorable kinetics and the best correlation with Aβ amyloid burden as compared with the other Aβ radiotracers) confirmed its ability to rule out AD with a specificity of 100%.59 On January 25, 2011, the preliminary FDA panel review of florbetapir for clinical use in AD made an initial recommendation for approval, but the final decision is pending.62 The recommendation for approval was conditional upon training being provided to ensure that physicians can accurately and consistently read the scans, since inconsistent scoring among raters was noted in early studies.62 This technique is anticipated to play a vital role in identifying AD, tracking its progression, assisting in differential diagnosis of cognitive deficit, and identifying patients who might benefit from Aβ-targeting therapies.59 Computer-Assisted Diagnosis As noted previously, the 3D-SSP software programs can greatly augment performance of physicians interpreting the studies. This has been taken a step further with the development of fully automated software that examines certain regions of interest in the brain to make a diagnosis.63 These programs show promise in distinguishing between AD and DLB, as well as other causes of dementia.63 Figure 7. Perfusion SPECT imaging in 3 axial sections in a patient with frontotemporal dementia demonstrates hypoperfusion of frontal and temporal cortices. Abbreviation: SPECT, single-photon emission computed tomography. Reproduced with permission from J Neurol Neurosurg Psychiatry Abbreviation: SPECT, single-photon emission computed tomography.

11 Nuclear Medicine Imaging in Dementia Conclusion The workup of dementia in hospitalized patients is complex and detailed. Recent developments in biomarkers of AD and other neurodegenerative dementias have identified the potential role of molecular brain imaging with F-FDG PET and perfusion SPECT in this workup, while highlighting the current and continuing role of CSF analysis, vmri, and a thorough cognitive assessment. Nuclear imaging techniques provide the opportunity to objectively evaluate a patient s disease burden and assist with difficult differential diagnosis. Although these techniques have not yet been widely accepted, it is expected that their feature in the recently proposed NINCDS-ADRDA criteria for the diagnosis of AD, as well as the attention to the field garnered by the recent FDA approval of DaTSCAN and preliminary approval of florbetapir, will stimulate thoughtful discussion about how best to integrate these techniques into clinical practice. 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