Accepted Manuscript Title: Brain Fluorodeoxyglucose (FDG) PET in dementia Author: Takashi Kato Yoshitaka Inui Akinori Nakamura Kengo Ito PII: DOI: Reference:

S1568-1637(16)30011-3 http://dx.doi.org/doi:10.1016/j.arr.2016.02.003 ARR 641

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Ageing Research Reviews

Received date: Revised date: Accepted date:

22-12-2015 8-2-2016 8-2-2016

Please cite this article as: Kato, Takashi, Inui, Yoshitaka, Nakamura, Akinori, Ito, Kengo, Brain Fluorodeoxyglucose (FDG) PET in dementia.Ageing Research Reviews http://dx.doi.org/10.1016/j.arr.2016.02.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

/1 Ageing Research Review Manuscript Number: ARR-D-15-00160 Review article

Brain Fluorodeoxyglucose (FDG) PET in dementia

Takashi Kato 1)2), Yoshitaka Inui 1), Akinori Nakamura 2) and Kengo Ito 1)2)3) 1) Department of Radiology, National Center for Geriatrics and Gerontology, National Center for Geriatrics and Gerontology 2) Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology 3) Innovation Center for Clinical Research, National Center for Geriatrics and Gerontology

Corresponding author: Takashi Kato E-mail: [email protected] Address: 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan

Highlight A selective and concise review of FDG PET in dementia imaging is described.

/2 Abstract The purpose of this article is to present a selective and concise summary of fluorodeoxyglucose (FDG) positron emission tomography (PET) in dementia imaging. FDG PET is used to visualize a downstream topographical marker that indicates the distribution of neural injury or synaptic dysfunction, and can identify distinct phenotypes of dementia due to Alzheimer's disease (AD), Lewy bodies, and frontotemporal lobar degeneration. AD dementia shows hypometabolism in the parietotemporal association area, posterior cingulate, and precuneus. Hypometabolism in the inferior parietal lobe and posterior cingulate/precuneus is a predictor of cognitive decline from mild cognitive impairment (MCI) to AD dementia. FDG PET may also predict conversion of cognitively normal individuals to those with MCI. Age-related hypometabolism is observed mainly in the anterior cingulate and anterior temporal lobe, along with regional atrophy. Voxelbased statistical analyses, such as statistical parametric mapping or three-dimensional stereotactic surface projection, improve the diagnostic performance of imaging of dementias. The potential of FDG PET in future clinical and methodological studies should be exploited further.

Keywords: FDG PET Alzheimer's disease Mild cognitive impairment Fluorodeoxyglucose preclinical AD dementia

/3 1

Introduction

2-[fluorine-18]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) (Phelps et al., 1979) is used to visualize cerebral glucose metabolism, which increases with regional synaptic activity and decreases with synaptic dysfunction or neural degeneration. As a functional imaging marker, FDG PET is useful for early or differential diagnosis of dementia. Current trends in dementia research are focused on asymptomatic or preclinical stages of Alzheimer's disease (AD), registries for various purposes, and multi-center cohort or clinical trials, in addition to pathophysiological investigations of various dementias. The goal of this article is to present a selective and concise summary of the use of FDG PET in dementia, including differential diagnosis of dementia, prediction of cognitive decline during progression of AD, as well as an observation of technical issues. Understanding these issues will help further improve the acumen of clinical research in dementia using FDG PET.

2

FDG PET scan

2.1

Biological basics of FDG PET

FDG PET plays a major part in clinical assessment for cancer diagnosis. However, the first application of FDG PET was brain imaging (Phelps et al., 1979). The main metabolic substrate for energy production in the brain is glucose. PET imaging of cerebral glucose metabolism using [18F]FDG is an application of the autoradiographic method that uses [14C]deoxyglucose as a tracer for glucose exchange between plasma and the brain, as well as phosphorylation of glucose by hexokinase in tissues (Sokoloff et al., 1977). FDG is phosphorylated to produce the metabolite FDG-6-phosphate. The

/4 [14C]deoxyglucose method has demonstrated that energy metabolism increases almost linearly with the degree of functional activation, i.e., spike frequency, in the terminal projection zones of activated pathways. Based on the astrocyte–neuron lactate shuttle hypothesis in which astrocytes and not neurons metabolize glucose (Pellerin and Magistretti, 1994), several studies have described neuron–glia metabolic coupling in which astrocytes detect synaptic activity and couple it to the delivery of energy substrates to neurons (Belanger et al., 2011). The local consumption of FDG reflects the energy demands at rest, during functional activation, as well as during pathological processes that affect neurons and synapses, including those in glia.

2.2

Protocols for FDG PET scanning

FDG PET scans are an in vivo application of the autoradiographic method. A dynamic 3D scan usually consists of six 5-min fames beginning 30 min after venous injection of FDG as applied in the Alzheimer's disease neuroimaging initiative (ADNI) (Weiner et al., 2010) and the Japanese Alzheimer's disease neuroimaging initiative (J-ADNI) (Iwatsubo, 2010). According to the standard procedure of ADNI and J-ADNI, while fasting for least 4 hours, subjects are allowed to rest comfortably in a dim room for 20 min to allow the [18F]FDG to be incorporated into the brain. During the uptake period, the patient’s eyes should be open, and the ears should remain un-occluded. Methodological standardization of the PET scan is important to utilize FDG PET as an imaging biomarker in clinical practice or trials (Mosconi et al., 2008b) (Ishii et al., 2006a). The European Association of Nuclear Medicine procedural guidelines for PET

/5 brain imaging recommend a standardized acquisition protocol with a fixed time for starting the acquisition (e.g., 30 min or 60 min after injection) (Varrone et al., 2009).

2.3

Visual interpretation and quantitative approaches

Statistical parametric mapping (SPM) (Friston et al., 1991) is a method that has been widely used in research to statistically analyze brain PET images, single photon computed tomography (SPECT), magnetic resonance (MR) images, and magnetoencephalography on a voxel-by-voxel basis. Three-dimensional stereotactic surface projection (3D-SSP) (Minoshima et al., 1995) has also been widely used for research and clinical diagnosis as a method for statistical voxel-by-voxel Z score mapping of FDG PET and cerebral blood flow (CBF) SPECT brain images. The SPM maps or 3D-SSP Z-score maps improve the diagnostic performance for imaging in dementia (Lehman et al., 2012; Minoshima et al., 1997; Perani et al., 2014). Moderate to high inter-rater concordance in evaluation of FDG PET in mild cognitive impairment (MCI) was achieved using a systematic interpretation method utilizing statistical mapping (Yamane et al., 2014). Various automated diagnostic quantitative and semiquantitative approaches have been developed and evaluated (Arbizu et al., 2013; Herholz et al., 2002; Herholz et al., 2011; Ishii et al., 2006b; Pagani et al., 2015). However, for predicting conversion from MCI to AD, these approaches are less sensitive albeit more specific than visual reading (Ito et al., 2015; Morbelli et al., 2015). A combined visual and semiquantitative evaluation improves the diagnostic accuracy for detection of an AD-like hypometabolic pattern in patients with MCI.

/6 3

FDG PET imaging in AD AD is a neurodegenerative disease that is pathologically characterized by amyloid

plaques and neurofibrillary tangles. AD is a clinical continuum that includes AD dementia, prodromal AD (MCI), and preclinical AD (cognitively normal). Patients with preclinical AD are cognitively unimpaired but carry AD pathology.

3.1

FDG PET in research criterion of AD

Diagnostic imaging, including PET, MR imaging, and X-ray computed tomography, is not used for the diagnostic criteria of AD such as National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984) or Diagnostic and Statistical Manual of Mental Disorders IV text revision (DSM-IV-TR). However, research criteria for these imaging methods have now been proposed by the National Institute of Aging and Alzheimer’s Association (NIA-AA) and the International Working Group (IWG).

3.1.1

NIA-AA (2011)

The working group of NIA-AA published new guidelines for diagnosing AD in 2011(Jack et al., 2011). The guidelines cover the full range of AD stages, from the asymptomatic stage through the most severe stages of dementia, and define three stages in a clinical continuum: preclinical AD (Sperling et al., 2011), MCI (Albert et al., 2011), and AD dementia (McKhann et al., 2011). For the diagnostic research criteria for MCI and AD dementia, the guidelines include two types of biomarkers that represent pathophysiological processes of AD, amyloid-beta and tau-mediated neural injury.

/7 Amyloid PET and the cerebrospinal fluid A1-42 levels are used to determine biomarkers for amyloid-beta deposition. The cerebrospinal fluid tau levels, FDG PET images, and MR images are biomarkers for tau-mediated neural injury. Based on the combination of results from these two types of biomarkers, the NIA-AA criteria for MCI and AD dementia provide four levels of probabilistic likelihood that the symptom is due to AD: unlikely, intermediate, high, and non-informative.

3.1.2

IWG-2

In 2007, the IWG for New Research Criteria for the Diagnosis of AD and the US NIAAA have contributed criteria for the diagnosis of AD that better define the clinical phenotypes and integrate biomarkers into the diagnostic process (Dubois et al., 2007). In 2014, they proposed revised research diagnostic criteria for AD (IWG-2) to improve the diagnostic framework. The AD diagnosis was simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and two types of biomarkers (Dubois et al., 2014). One is a pathophysiological biomarker that is consistent with the presence of Alzheimer’s pathology. The other one is a downstream topographical biomarker that better serves as a measurement for monitoring the course of disease. FDG PET is utilized as a downstream topographical biomarker, along with volumetric MR imaging. “Topographical” is indicative of the regional distribution of Alzheimer’s pathology, including medial temporal lobe atrophy on MR images or reduced glucose metabolism in parietotemporal regions on FDG PET images. The IWG-2 proposes that a diagnostic change indicative of typical AD need only be based on pathophysiological markers, such as cerebrospinal fluid markers (A1-42, T-

/8 tau, and P-tau) and amyloid PET. FDG PET is a better method for monitoring the course of the disease than for determining disease etiology. For atypical AD cases, such as the frontal variant, posterior variant, and logopenic variant of AD, topographical markers can help clinicians characterize the clinical phenotype (regional cortical hypometabolism in FDG PET), whereas a positive pathophysiological biomarker is required to link the phenotype to the underlying Alzheimer’s pathology. However, the IWG-2 acknowledges the ability of FDG PET to differentiate AD dementia from other neurodegenerative dementias. 3.2

Findings in AD dementia

The main FDG PET findings in AD dementia are hypometabolism in the parietotemporal association area, posterior cingulate cortices, and precuneus (Minoshima et al., 1995) (Figure 1). Glucose metabolism is usually preserved in the primary motorsensory cortices, primary visual cortices, striatum, thalamus, and cerebellar hemispheres. The frontal association cortex may also be involved, but this is more variable. Involvement of the frontal association cortex is often observed during the progression of AD dementia, but is not common in early or mild AD (Herholz et al., 2007). The areas showing hypometabolism in AD dementia, the medial frontal gyrus, precuneus, and inferior parietal lobule, are closely related to functional connectivity within the defaultmode network areas (Passow et al., 2015). Patients with early-onset AD (onset 65 years) (Kim et al., 2005; Sakamoto et al., 2002). Earlyonset AD patients usually have a more severe clinical presentation compared with those

/9 with late-onset AD (Lawlor et al., 1994). This phenomenon likely reflects the different subtypes of AD (Whitwell et al., 2012) and greater cognitive reserves in younger compared with older subjects.

3.3

MCI

MCI is a syndrome that is thought to be a transition phase between healthy cognitive aging and dementia, and includes many subjects in the prodromal phase of AD (DeCarli, 2003). The role of FDG PET in MCI is to assess the pathophysiology in relation to the symptoms and predict the likelihood of converting from MCI to AD dementia (Ito et al., 2015). Many studies have demonstrated that hypometabolism in the inferior parietal lobe, precuneus, and posterior cingulate is a predictor of conversion from MCI to AD dementia (Figure 2). Yuan and colleagues published the first systematic review comparing the ability of FDG PET, CBF SPECT, and structural MR imaging to predict short-term conversion to AD in patients with MCI (Yuan et al., 2009). FDG PET pooled estimates exhibited 88.8% sensitivity (95% confidence interval (CI), 82.2-93.6%) and 84.9% specificity (95% CI, 78.1-90.3%); CBF SPECT exhibited 83.8% sensitivity (95% CI, 82.2-93.6%) and 70.4% specificity (95% CI, 62.9-77.2%); and structural MRI exhibited 72.8% sensitivity (95% CI, 65.1-79.6%) and 81% specificity (95% CI, 65.1-79.6%). The results showed that FDG PET performs slightly better than SPECT and structural MR imaging for predicting the conversion to AD in patients with MCI; similar performance was found between SPECT and MR imaging.

/ 10 Zhang et al. performed a meta-analysis to estimate the diagnostic accuracy of FDG PET and [11C]Pittsburgh Compound B (PiB), an amyloid imaging tracer PET (Mathis et al., 2003) for predicting the conversion to AD dementia in patients with MCI over a followup period of 1-3 years (Zhang et al., 2012). FDG PET pooled estimates exhibited 78.7% sensitivity and 74.0% specificity; PiB PET pooled estimates exhibited 93.5% sensitivity and 56.2% specificity. FDG PET has a lower sensitivity and a higher specificity than PiB PET. PiB positivity indicates that the individual exhibits amyloid pathology in the brain, but it reflect the presence of neuronal or synaptic injury. Normal cerebral metabolism in patients with MCI suggests that downstream synaptic dysfunction or neurodegeneration has not yet started or that compensatory mechanisms have not been exhausted, leading to the high specificity in predicting the conversion. Some reports (Landau et al., 2010; Nobili et al., 2008) included in the meta-analysis by Zhang showed that FDG PET has a relatively lower predicting performance with 82% sensitivity and 70-73% specificity compared with previous studies. One reason may be the older age of the subjects with MCI who were recruited in the studies by Landau et al. and Nobili et al. The mean age of the MCI subjects was over 75 years, and these subjects may have shown decreased levels of AD-like hypometabolism than the relatively younger subjects with MCI (mean age

Brain fluorodeoxyglucose (FDG) PET in dementia.

The purpose of this article is to present a selective and concise summary of fluorodeoxyglucose (FDG) positron emission tomography (PET) in dementia i...
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