Brain FDG PET and the diagnosis of dementia.

N u c l e a r M e d i c i n e a n d M o l e c u l a r I m a g i n g • R ev i ew Shivamurthy et al. Use of FDG PET in Diagnosing Dementia

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Nuclear Medicine and Molecular Imaging Review

Brain FDG PET and the Diagnosis of Dementia Veeresh K. N. Shivamurthy 1 Abdel K. Tahari1 Charles Marcus1 Rathan M. Subramaniam1,2,3 Shivamurthy VKN, Tahari AK, Marcus C, Subramaniam RM

OBJECTIVE. We review the role of brain FDG PET in the diagnosis of Alzheimer disease, frontotemporal dementia, dementia with Lewy bodies, and vascular dementia. Characteristic spatial patterns of brain metabolism on FDG PET can help differentiate various subtypes of dementia. CONCLUSION. In patients with different subtypes of dementia, FDG PET/CT shows distinct spatial patterns of metabolism in the brain and can help clinicians to make a reasonably accurate and early diagnosis for appropriate management or prognosis.

D

Keywords: Alzheimer disease, dementia, FDG PET DOI:10.2214/AJR.13.12363 Received December 10, 2013; accepted after revision April 11, 2014. R. M. Subramaniam is supported by an RSNA–GE Healthcare Education Scholar Grant. 1 Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, JHOC 3235, 601 N Caroline St, Baltimore, MD 21287. Address correspondence to R. M. Subramaniam ([email protected]). 2

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD. 3 Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

WEB This is a web exclusive article. AJR 2015; 204:W76–W85 0361–803X/15/2041–W76 © American Roentgen Ray Society

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ementia is characterized by progressively deteriorating dysfunction of various intellectual domains: memory, language, and executive function. There were an estimated 35.6 million people with Alzheimer disease (AD) and other dementias worldwide in 2009 [1]. With the rapid aging of societies around the globe, the number of people with dementia is projected to reach 66 million by 2030 [2]. The prevalence of dementia increases with age [3]. The global economic cost of dementia in 2010 was estimated at U.S. $604 billion [2]. In clinical practice, clinical criteria for AD are considered to be the basis of the diagnosis. Clinical diagnosis, even when combined with any of the neuropsychological tests available, is neither sensitive nor specific enough to be considered as a reference standard in diagnosing dementia. FDG PET is a biomarker for neuronal degeneration in dementia [4], in addition to being an oncologic imaging biomarker [5–9]. Studies have shown that the appropriate use of FDG PET for evaluating patients with dementia can add valuable information to the clinical workup without adding to the overall costs of evaluation and management [10]. The purpose of this article is to review the value of FDG PET as a tool to diagnose neurodegeneration and its applicability in differentiating among various types of dementia. Glucose Use Patterns: Normal and Alterations With Aging Several studies have been published evaluating glucose use patterns in healthy sub-

jects. Glucose use in the cerebral hemispheres is usually symmetric (Fig. 1), and the mean glucose use patterns of the cortex, caudate, and thalamus are equal in subjects of all ages [11]. With normal aging, the largest FDG uptake decrease has been observed bilaterally in the superior medial frontal, motor, anterior, and middle cingulated cortexes; bilateral parietal regions (with left-sided predominance); and superior and inferior parietal cortexes. The metabolic rate of the superior temporal pole extending to the insular and orbitofrontal cortexes is especially affected. The smallest glucose uptake decrease is observed in the bilateral medial temporal lobes (hippocampus, amygdale, and parahippocampal gyrus). The putamen, pallidum, and lateral thalamic nuclei, as well as the right posterior cingulate cortexes, precuneus, bilateral occipitotemporal cortex, and cerebellum, are metabolically less impaired [12]. Interpretation of Brain FDG PET: Qualitative and Quantitative Clinical interpretation of FDG PET can be performed qualitatively along with quantitative analysis to aid the reader. The FDG metabolism of the superficial and deep gray matter is compared to identify areas of decreased metabolism and then compared for left-to-right symmetry. Any focal area or left-to-right asymmetry of hypometabolism is correlated to identify a spatial pattern of hypometabolism compatible with various types of dementia. The quantitative analyti-

AJR:204, January 2015


Use of FDG PET in Diagnosing Dementia Fig. 1—46-year-old woman who underwent FDG PET/ CT study of brain and whose findings were normal. A and B, Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show normal brain metabolism and no evidence of significant hypometabolism (> 1 SD) for age-matched population. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). A = anterior, P = posterior.

A

B

A

B cal software used for this manuscript’s figures (Cortex ID, GE Healthcare) involves the following steps. Anatomic standardization of the PET image is performed by realigning the images in a standard stereotactic orientation using a standard brain atlas. A 3D

stereotactic surface projection is then used to extract regional cortical metabolic activity, which is an alternative approach to the conventional ROI analysis. The next step involves normalization of the available dataset to a reference region. The reference standard

Fig. 2—57-year-old woman with history of cognitive decline. A and B, Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show distinct hypometabolism in posterior cingulate cortex (right greater than left), feature consistent with amnestic mild cognitive impairment. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). A = anterior, P = posterior.

used is the region of the thalamus, which is thought to be least affected by the disease process of interest. The dataset is then compared with an available normal reference database by means of a z score formed on a pixel-by-pixel basis on the 3D stereotactic

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Shivamurthy et al. surface projection format. A positive z score represents reduced metabolic activity relative to the normal reference data. Each hemisphere is evaluated independently on the basis of the difference between the z score reduction in the association cortex and the z score reduction in the primary sensorimotor cortex. The data obtained are finally presented in the 3D stereotactic surface projection format for visual inspection. The individual z score data, as well as the extracted raw data, can be viewed from superior, inferior, right, left, anterior, posterior, and two medial aspects of the brain. A standard brain contour is added to the z score image to facilitate visual inspection [13]. Alzheimer Disease AD is the most common cause of dementia in elderly patients (≥ 65 years old) and is estimated to affect 8–10% of people who are older than 65 years [14]. The cognitive changes with AD tend to follow a characteristic insidious pattern, beginning with memory impairment and spreading to language, praxis, and visuospatial deficits [15]. It may be sporadic or may be associated with genetic factors, such as mutation in the amyloid precursor protein and the ε4 allele of the apolipoprotein E gene (APOΕ4) [16]. Cerebral glucose metabolic activity is an index of neuronal and synaptic function, and glucose hypometabolism is a typical feature of neurodegeneration. Current treatment options for AD include acetylcholine esterase inhibitors and N-menthyld-aspartate receptor antagonist (memantine), both of which aim at slowing progression and controlling symptoms. Newer drugs under development aim at modifying the pathologic TABLE 1: Diagnostic A ccuracies of Different Imaging Modalities and CSF Biomarkers in Alzheimer Disease Modality or Biomarker

Sensitivity

Specificity

MRI

83 (79–87)

85 (80–89)

CT

80 (68–88)

87 (78–93)

SPECT

79 (72–85)

84 (78–88)

PET/CT

91 (86–94)

85 (79–91)

CSF-Aβ

76 (72–80)

77 (72–82)

CSF-Tt

79 (75–83)

85 (81–89)

CSF-Pt

78 (73–83)

81 (76–85)

Note—Data are percentage (95% CI). This table is a summary of previously published data [24].

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steps leading to AD. Common adverse effects of acetylcholine esterase inhibitors include nausea, vomiting, diarrhea, sleep disturbances, muscle cramps, weakness, bradycardia, and urinary incontinence [17]. Clinical evaluation of dementia relies on various screening tests; however, a reference standard does not exist. The Mini-Mental State Examination [18], which is probably the most applied screening tool for dementia worldwide, has been criticized for its lack of sensitivity [19, 20] and for its dependency on age and level of education. Many studies have shown that clinical assessment of dementia has varying accuracies. Studies have shown a varying range of accuracies in diagnosing dementia, with a sensitivity ranging from 44% to 81% and specificity ranging from 77% to 98% [19–23]. A recent meta-analysis of 119 primary studies by Bloudek and colleagues [24] assessed the diagnostic value of various diagnostic biomarkers and advanced imaging strategies used to differentiate mild AD from non-AD dementias. Pooled meta-analysis of 27 studies evaluating FDG PET found 90% sensitivity (95% CI, 84–94%) and 89% specificity (95% CI, 81–94%). FDG PET also was more accurate in discriminating patients with AD from demented control subjects, including those with mild cognitive impairment (MCI), with 92% sensitivity (95% CI, 84–96%) and 78% specificity (95% CI, 69–85%) [24]. The diagnostic accuracy of PET/CT, MRI, CT, SPECT, and various CSF biomarkers from this meta-analysis is summarized in Table 1. FDG PET in Mild Cognitive Impairment Amnestic MCI is defined as subjective complaint of cognitive impairment with objective cognitive impairment adjusted for age but with preserved general intellectual function and activities of daily living [25, 26]. Brain imaging plays important roles in identifying other treatable causes of cognitive decline (e.g., subdural hematoma and normal pressure hydrocephalus), predicting the probability of developing dementia, and measuring progression of neurodegenerative disease [27]. A cross-sectional and longitudinal parallel cohort study design was conducted among 47 patients with amnestic MCI (mean [± SD] age, 72.4 ± 7.1 years) and 50 matched healthy control subjects who were clinically assessed with the Mini-Mental State Examination and other cognitive tests and who were followed for a mean of 34.0 ± 1.8 months. Dementia was later diagnosed in 13 of the 47 patients

with amnestic MCI, with a prevalence rate of 27.7%, considerably higher than that in the control group (2.0% [1/50]; p < 0.01). This significant conversion rate of amnestic MCI to AD shows the value of early investigation and diagnosis of amnestic MCI in the elderly [28]. In amnestic MCI, FDG PET shows a pattern of bilateral glucose hypometabolism in the limbic system, posterior cingulate (Fig. 2), parahippocampal gyri, and temporal lobes (inferior temporal gyrus) [29]. More specifically, a reduced cerebral metabolic rate for glucose use was found mainly in the posterior cingulate cortex, compared with patients with AD who had pronounced glucose hypometabolism in the precuneus, inferior parietal lobule, and middle temporal gyrus, along with the posterior cingulate cortex [30, 31]. A study by Kantarci et al. [32] included 25 patients with amnestic MCI at age 55–86 years and 25 age- and sex-matched cognitively healthy subjects who underwent FDG PET. They divided the subjects with amnestic MCI and cognitively healthy subjects into two groups: cognitively normal or amnestic MCI–young (age ≤ 73 years) and cognitively normal or amnestic MCI–old (age > 73 years). Glucose uptake was measured in these groups. A pattern of decreased glucose metabolism in the medial temporal, posterior cingulate, precuneus, lateral parietal, and temporal lobes in amnestic MCI–young subjects was consistent with the typical pattern observed in AD. However, glucose hypometabolism in amnestic MCI– old subjects predominantly involved the frontal lobes and the left parietal lobe [32]. Thus, it should be noted that patients older than 73 years presenting with amnestic MCI may show significant frontal lobe hypometabolism, which is a characteristic feature of advanced AD. Another study of 42 patients with amnestic MCI showed a significant correlation in all patients to the posteromedial cortex as a key node of the network that is involved in awareness of memory deficit [33]. The APOE gene has been shown to be a major genetic risk factor for late-onset Alzheimer disease [34]. APOE ε4 is associated with a dramatically increased risk of neurodegeneration, whereas APOE ε2 is shown to be associated with a decreased risk [35]. A study on cognitively normal APOE ε4 carriers 20–39 years old who underwent FDG PET showed significantly decreased glucose metabolism in the bilateral posterior cingulate cortex and other cortical regions [36]. Mosconi et al. [37] investigated 37 patients



Use of FDG PET in Diagnosing Dementia Fig. 3—81-year-old man with history of cognitive decline, over course of few months. A and B, Study was requested to evaluate for Alzheimer disease (AD) versus frontotemporal dementia. Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show hypometabolism in bilateral frontal, temporal, and parietal cortexes with sparing of sensory motor and occipital cortex, spatial distribution pattern typically seen in advanced stages of AD. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). A = anterior, P = posterior.

A

B

A

B diagnosed with amnestic MCI with baseline FDG PET scan, electroencephalography, and APOE genotyping. After 1 year, all patients were reevaluated for diagnosis and severity level. Eight of 37 (22%) patients with amnestic MCI converted to AD. All convert-

ers showed reduced glucose metabolism in the inferior parietal cortex as compared with the nonconverters. For all study patients with amnestic MCI, reduced glucose metabolism in the inferior parietal cortex predicted conversion to AD with 84% overall diagnostic

Fig. 4—72-year-old woman with history of anomia, gradually progressing memory impairment, cognitive decline, and gradual paucity of speech for past 2 years. A and B, Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show marked hypometabolism in frontal and anterior temporal lobes bilaterally, features consistent with frontotemporal dementia. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). A = anterior, P = posterior.

accuracy (p = 0.003). APOE ε4–positive converters had additional glucose metabolism reductions within the frontal areas, such as the anterior cingulate and inferior frontal cortex. Thus, improved prediction of the conversion of amnestic MCI to AD for the APOE ε4–



Shivamurthy et al. positive group, with 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), leads to excellent discrimination from APOE ε4–negative nonconverters [37]. FDG PET in Alzheimer Disease AD shows a higher number of regions with hypometabolism compared with amnestic MCI. These include the bilateral temporal lobes (middle and inferior temporal gyri), limbic system (parahippocampal gyrus and posterior cingulate gyrus), parietal lobe, and, rarely, occipital structures [29, 38]. Areas of low glucose metabolism in the posterior cingulate cortex were wider in AD than in amnestic MCI and extended to the precuneus, whereas low glucose metabolism was found in the lateral parietal cortex in patients with AD but not in those with amnestic MCI. Individual subject pattern analysis revealed that 86% of patients with AD had low glucose metabolism in the posterior cingulate cortex (including the precuneus in 71%), 71% in the temporal cortex, 64% in the parietal cortex, and 35% in the frontal cortex [30]. In another study, temporoparietal hypometabolism was shown to be more sensitive (sensitivity, 93.6%; specificity, 50%; p = 0.003), but posterior cingulate hypometabolism was more specific (sensitivity, 74.2%; specificity, 71.4%; p = 0.01) for diagnosing AD [39]. Hypometabolism in the temporoparietal and posterior cingulate regions was found much more frequently in AD than frontotemporal lobar dementia (FTD) (odds ratio, 14.5 and 7.2, respectively) [39]. Patients with advanced AD show a consistent pattern of reduced glucose metabolism in the precuneus, posterior cingulate cortex, and parietotemporal regions, extending to the prefrontal cortex along with advancing disease [40] (Fig. 3), sparing the precentral gyrus and occipital cortex. Frontotemporal Lobar Dementia FTD is one of the most common forms of dementia in individuals younger than 65 years. In 2011, it was estimated that there were approximately 20,000–30,000 patients with cognitive syndromes of FTD in the United States [41]. Unlike the incidence of AD, which increases markedly with age, it is rare to have the onset of FTD after age 75 years. Compared with AD, FTD has the early appearance of behavioral symptoms, such as difficulty in maintaining socially appropriate conduct, and apathy is more pervasive [42]. According to the consen-

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sus criteria, FTD is subdivided into the behavioral variant of FTD, semantic dementia, and nonfluent progressive aphasia [43]. Behavioral and language manifestations are core features of the behavioral variant of FTD. Patients have relatively preserved memory, which differs from patients with AD. Patients with semantic dementia often present with the complaint of word-finding difficulties. Progressive nonfluent aphasia presents with nonfluent and hesitant speech [44]. No drugs have been shown to be clearly effective in FTD [45]. Certain drugs can have adverse effects on patients with FTD and should be used with caution. Cholinesterase inhibitors can worsen behavioral symptoms and have been shown to intensify irritability and restlessness in patients with FTD and, thus, should be avoided [46, 47]. Donepezil may lead to behavioral worsening through its mild activation and alerting properties, thus exacerbating psychiatric symptoms in patients with FTD [46]. The accuracy of the clinical evaluation of FTD was analyzed by Mendez et al. [46]. The sensitivities and specificities for the diagnosis of FTD were 37% and 100%, respectively, for consensus clinical criteria; 64% and 70%, respectively, for MRI; and 91% and 75%, respectively, for SPECT/PET scans. Positive and negative predictive values were 100% and 64%, respectively, for consensus criteria; 65.6% and 68.5%, respectively, for MRI; and 76% and 90%, respectively, for SPECT/PET. These results show that SPECT/PET had the greatest negative predictive value over consensus criteria and MRI [46]. Patients with FTD show decreased glucose metabolism, typically in the frontal lobe and anterior temporal lobe [48] (Fig. 4). A conjunct analysis of FDG PET images in 29 patients with FTD in comparison with age-matched control subjects identified ventromedial frontopolar cortex as the single region where significant metabolic impairment was found. This region was situated above the supraorbital sulcus, in the right frontopolar gyrus [49]. In early stages of FTD, glucose hypometabolism is limited to the frontal lobes. During the progression of the disease, pathologic changes are seen to spread into the parietal and temporal cortexes [50]. As the disease progresses, FTD shows widespread areas of decreased metabolism involving bilateral prefrontal areas, including the dorsolateral frontal, orbitofrontal, and medial frontal areas and anterior or ventral temporal regions and subcortical

structures, including the basal ganglia (putamen and globus pallidus) and medial thalamic regions [51]. Although significant metabolic abnormalities in FTD are predominant in the frontal anterior temporal lobes and the subcortical structures, they can be more pervasive to most brain regions and can mimic AD [51]. Interpretation of FDG PET in the absence of hypometabolism in regions typically affected in AD before considering FTD has been shown to misclassify a significant portion of FTD. Womack et al. [39] have shown that hypometabolism in the anterior cingulate (specificity, 93.6%; p < 0.001) and anterior temporal cortexes (specificity, 80.7%; p < 0.001) have higher specificities and higher likelihood ratios for a diagnosis of FTD than hypometabolism in the temporoparietal cortex has for AD (specificity, 50.0%; p = 0.003). Progressive nonfluent aphasia has been considered as one of the clinical syndromes subsumed under FTD. Patients present with word-finding difficulties, motor speech impairment, and agrammatism, with relative sparing of single-word comprehension and semantic memory [52]. In a group of patients (n = 10) with progressive nonfluent aphasia, cerebral glucose metabolism was measured using FDG PET. Compared with control subjects, the patients showed hypometabolism in several regions, most notably in the left anterior insula and frontal opercular region. When the progressive nonfluent aphasia group was compared with a group with AD (n = 10), the distinct persistent hypometabolic region was shown to be the left anterior insula only [53]. In contrast to nonfluent aphasia, patients with semantic dementia have difficulty in word comprehension, disinhibition, obsessions, and compulsions [54]. Kim et al. [55] recently published a study of 28 subjects (mean age, 67.3 ± 8.4 years) who met the clinical diagnostic criteria for semantic dementia. Brain MRI and FDG PET scans were performed in all patients. Compared with control subjects (63 healthy volunteers), patients with semantic dementia had decreased glucose metabolism in the bilateral anterior temporal lobes (worse on the left side), the left inferior temporal lobe, the left lateral temporal areas, and the bilateral orbitofrontal lobes (p < 0.05) [55]. Diehl and colleagues [56] observed a characteristic pattern of cerebral glucose metabolism in semantic dementia distinct from that in FTD. Patients with FTD as a group showed an



Use of FDG PET in Diagnosing Dementia

A

Fig. 5—78-year-old man who presented with recent history of episodes of confusion, progressive cognitive decline, memory loss, and dysphasia. Along with these symptoms, he was also noticed to have features of parkinsonism, for which he was started on trial of carbidopa and levodopa. A and B, Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show symmetric diffuse hypometabolism in cerebral hemispheres in frontal, temporal, parietal, and occipital cortex with sparing of sensorimotor cortex. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). Hypometabolism of occipital cortex is typical of dementia with Lewy bodies. A = anterior, P = posterior.

B

A

B extensive slightly asymmetric (right greater than left) hypometabolism of the frontal lobe, which spared the motor cortex. Patients with semantic dementia as a group showed hypometabolism over the whole left temporal lobe and in the right temporal pole [56].

Dementia With Lewy Bodies Typical dementia with Lewy bodies is characterized by visual hallucinations, parkinsonism, fluctuating alertness, and falls [57]. The prevalence of dementia with Lewy bodies is estimated to be 4.2% of all dementia cases in

Fig. 6—29-year-old woman who presented with 2-week history of general lethargy and slow speech. A and B, Three-dimensional stereotactic surface projection images of FDG metabolism (A) and FDG hypometabolism (B) of brain show hypometabolism in bilateral temporal and occipital lobes, more pronounced in occipital cortexes, spatial distribution pattern suggestive of dementia with Lewy bodies. Age-matched z score was compared with normal database (Cortex ID software, GE Healthcare). A = anterior, P = posterior.

the community and steeply increases to 7.5% in secondary-care settings [58]. Memory loss occurs early in dementia with Lewy bodies, as opposed to extrapyramidal motor symptoms, which are more pronounced in Parkinson dementia. There are currently no disease-mod-



Shivamurthy et al. ifying drugs that are effective for dementia with Lewy bodies, and it is primarily treated symptomatically. Drugs used include cholinesterase inhibitors, memantine, and dopaminergic therapies. Standard neuroleptics can cause impaired consciousness, irreversible parkinsonism, or autonomic dysfunction and are contraindicated. Atypical antipsychotics can be used with caution, because of the possibility of anticholinergic effects, exacerbation of extrapyramidal symptoms, and worsening cognitive impairment. Given the presentation with psychotic symptoms and contraindications to standard antipsychotic drugs, it is important to diagnose dementia with Lewy bodies early in its course [59]. Clinical diagnostic criteria for dementia with Lewy bodies based on clinical features have shown high specificity (> 80%) but variable, and sometimes unacceptably low, sensitivity (< 30%) [60, 61]. Hence, there is a need to develop ways of improving the sensitivity of the diagnosis of dementia with Lewy bodies without a loss of specificity. Molecular imaging plays a key role in supporting the clinical diagnosis of dementia with Lewy bodies. FDG PET shows a typical pattern of hypometabolism, which involves the occipital cortex (Figs. 5 and 6) and typically spares the posterior cingulate cortex [62]. Other regions of hypometabolism noted in dementia with Lewy bodies are mainly in the temporal and parietal cerebral cortexes [63]. Delusions are frequent in dementia with Lewy bodies, and significant relative hypometabolism of the right prefrontal cortex was found in patients with dementia with Lewy bodies with delusions [64]. The visual hallucinations that are a clinical symptom of dementia with Lewy bodies are likely correlated with a reduction in cerebral glucose metabolism in the primary visual cortex (Brodmann areas 17–19) [65]. It should be noted that metabolic activity in the primary visual cortex is usually well preserved in AD. No differences were found in other regions commonly affected in AD, including the superior parietal lobe, lateral temporal lobe, and prefrontal region [66]. Occipital hypometabolism has been shown to be a potential antemortem marker that distinguishes dementia with Lewy bodies from AD [65]. In a study, patients with autopsy-confirmed AD and dementia with Lewy bodies both showed significant metabolic reduction involving parietotemporal association, posterior cingulate, and frontal association cortexes. Patients with dementia with Lewy bodies

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TABLE 2: Summary of Distinct Spatial Patterns of Glucose Uptake in FDG PET in Different Types of Dementia Type of Dementia

Characteristic Spatial Pattern of Hypometabolism on FDG PET

Amnestic mild cognitive impairment

Posterior cingulate cortex and parahippocampal gyri plus inferior temporal gyrus [29].

Alzheimer disease

Limbic system (parahippocampal gyrus and posterior cingulate gyrus), extending to precuneus plus bilateral temporal lobes (middle and inferior temporal gyri) plus posterior parietal cortex [30, 38]. Typically spares the precentral gyrus and occipital lobe.

Advanced Alzheimer disease

Posterior cingulate cortex, precuneus, and parietotemporal regions, extending to the frontal cortex [40].

Frontotemporal dementia

Ventromedial and anterior portions of the frontal lobe involving bilateral prefrontal areas and anterior and ventral temporal regions, extending into subcortical structures and medial thalamic regions, as the disease progresses [39, 49].

Lewy body dementia

Occipital cortex (primary visual cortex) plus temporal and parietal cerebral cortexes, typically sparing the posterior cingulate cortex [62, 65].

Vascular dementia

Focal cortical, subcortical, deep gray nuclei, and cerebellar hypometabolism [69, 71].

showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (29% for dementia with Lewy bodies vs 8% for AD). Two of 40 patients (5%) with probable AD showed metabolic reduction in the primary visual cortex, compared with two of nine (22%) patients with possible dementia with Lewy bodies and three of four (75%) patients with probable dementia with Lewy bodies, yielding a specificity of 88% and sensitivity of 62% (z = −2.0) and specificity of 95% and sensitivity of 38% (z = −2.5), respectively, for the discrimination of clinically diagnosed AD versus possible and probable dementia with Lewy bodies [65]. Vascular Dementia Vascular dementia (VaD) represents the second most common type of dementia after AD. It is characterized by sudden variable initial symptoms, such as apathy, falls, and focal weakness [67]. It broadly follows three clinicopathologic processes: multiinfarct dementia, single strategic infarct dementia, and subcortical dementia. There are no drugs specific for the treatment or prevention of VaD. Acetylcholinesterase inhibitors and memantine have been shown to have small positive effects on cognition in patients with VaD. The adverse effects of these drugs have been discussed in previous sections of this article [68]. CT and MRI are able to detect morphologic lesions but cannot determine functional consequences of the underlying pathologic abnormalities. FDG PET

can show scattered areas of focal cortical and subcortical hypometabolism and can effectively differentiate VaD from AD [69]. VaD is at times associated with AD or other neurodegenerative disorders. These patients should be examined with FDG PET to determine the comorbidity of AD or other neurodegenerative abnormalities [70]. Kerrouche et al. [71] used a voxel-based multivariate analysis of FDG PET performed on 153 subjects to separate patients with VaD or AD from age-matched control subjects. Lower metabolism in the deep gray nuclei, cerebellum, primary cortexes, middle temporal gyrus, and anterior cingulate cortex differentiated VaD from AD, whereas lower metabolism in the hippocampal region, orbitofrontal, posterior cingulate, and posterior parietal cortexes separated AD from VaD. Hypometabolic patterns common to VaD and AD were shown to be the posterior parietal, precuneus, posterior cingulate, prefrontal, and anterior hippocampal regions. This analysis separated VaD from AD with a 100% accuracy and separated healthy control subjects from demented subjects with 72% sensitivity and 96% specificity [71]. The characteristic patterns of glucose hypometabolism in the different types of dementia has been briefly summarized in Table 2. Limitations of FDG PET in Dementia Biologic Parameters Patient motion can be substantial and should be recognized because it can affect the quality of the images, leading to misin-



Use of FDG PET in Diagnosing Dementia terpretation [72]. Especially in the analysis of small brain structures, head motion results in inaccuracies of quantified data. The implementation of the multiacquisition frame method and an event-by-event method to correct PET data for motion are advised to overcome these errors [73]. The influence of hyperglycemia on the cerebral FDG distribution patterns was studied by Kawasaki and coworkers [74]. In statistical parametric mapping analysis, hyperglycemia was found to affect the cerebral distribution patterns of FDG. The FDG uptake was relatively decreased in the gray matter, mainly in the posterior cingulate, precuneus, and frontal, temporal, and parietal association cortexes, resembling those observed in AD. For mild hyperglycemia, those authors recommended the cerebellar cortex as the reference region to detect decreased uptake patterns, with an emphasis on optimal glucose control [74]. Mixed brain abnormalities in dementia can coexist in huge magnitude and can potentially limit the specificity of studies correlating FDG PET findings with postmortem diagnoses [75, 76]. Amyloid PET/CT in the Diagnosis of Dementia A detailed discussion of amyloid PET in dementia is beyond the scope of this review. However, a brief synopsis is presented. Because amyloid-β plaques are the hallmark of AD, much effort has gone into the field of amyloid imaging, and it is being considered for the diagnosis of AD. Different radiotracers for amyloid-PET have been introduced. The Pittsburgh compound B (11C-PIB) was the first tracer to be described and extensively studied. It is a derivative of thioflavin-T amyloid dye and binds with high affinity and high specificity to neuritic amyloid-β plaques [77, 78]. However, the short 20-minute half-life of 11C limits routine clinical use and requires an on-site cyclotron, whereas the 110-minute half-life of 18F-labeled amyloid PET ligands allows incorporation of PET into routine clinical practice, as has occurred with FDG [79]. The U.S. Food and Drug Administration has approved 18F-florbetapir and 18F-flutemetamol for brain amyloid PET [79, 80]. Both 18 F-florbetapir and 18F-flutemetamol have proven to be effective in imaging amyloid-β fibrillar abnormalities in vivo [81, 82]. For clinical purposes, the brain amyloid PET scans are read qualitatively as negative or positive for moderate-to-severe amyloid-β fibrillar amyloid deposition. There is more nonspecific binding in the white matter than

gray matter, illustrating a “gray-white differentiation” in a negative study. When there is significant gray matter uptake, the gray-white differentiation is lost, and the study becomes positive for moderate-to-severe amyloid-β fibrillar amyloid deposition. Because healthy individuals without cognitive symptoms can have a positive study, the real clinical value of amyloid imaging, at this stage, is a negative study, which effectively excludes moderate-to-severe amyloid-β fibrillar amyloid deposition and, thus, AD as a cause of dementia. Efforts are continuing to develop appropriate use criteria for brain amyloid PET and to define its value in patient management and prognosis [83, 84]. Conclusion In patients with different subtypes of dementia, FDG PET shows distinct spatial patterns of metabolism in the brain and can help clinicians to make a reasonably accurate early diagnosis, for appropriate management or prognosis. FDG PET shows a pattern of glucose hypometabolism in the posterior cingulate and parahippocampal gyri in amnestic MCI, gradually spreading to involve the bilateral temporal lobes (middle and inferior temporal gyri) and the parietal lobes in AD, extending to the prefrontal cortex with advancing disease. Metabolic abnormality in FTD is predominant in the frontal anterior temporal lobes and in the subcortical structures. FDG PET shows a characteristic pattern of hypometabolism involving the occipital cortex, typically sparing the posterior cingulate cortex in dementia with Lewy bodies. In VaD, FDG PET can show scattered areas of focal cortical and subcortical hypometabolism. FDG PET helps to achieve better diagnostic accuracy, earlier in the course of the disease, and can provide physicians with more-precise information regarding the prognosis and management of dementias. A negative amyloid brain PET is useful to exclude AD as a possible cause of dementia. References 1. Prince M, Ferri CP, Sousa R, et al. World Alzheimer report 2009. Alzheimer’s Disease International website. www.alz.co.uk/research/files/ WorldAlzheimerReport.pdf. Published 2009. Accessed August 28, 2014 2. Wortmann M. Dementia: a global health priority— highlights from an ADI and World Health Organization report. Alzheimers Res Ther 2012; 4:40 3. Breteler MM, Ott A, Hofman A. The new epidemic: frequency of dementia in the Rotterdam

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Brain fluorodeoxyglucose (FDG) PET in dementia.

Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting.

Brain 18F-FDG PET imaging in the differential diagnosis of parkinsonism.

Automated identification of dementia using FDG-PET imaging.

Differential diagnosis of posterior fossa brain tumors: Multiple discriminant analysis of Tl-SPECT and FDG-PET.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia.

FDG-PET in the selection of brain lesions for biopsy.

Diagnostic performance of an automated analysis software for the diagnosis of Alzheimer's dementia with 18F FDG PET.

Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis.

CT for ¹⁸F-FDG Brain Imaging in Patients Examined for Suspected Dementia.

Post-therapy normalization of brain FDG-PET in Morvan's syndrome.

CT study.

A comparison of FDG PET and IQNB SPECT in normal subjects and in patients with dementia.

Prediction of standard-dose brain PET image by using MRI and low-dose brain [18F]FDG PET images.

FDG-PET in pediatric posterior fossa brain tumors.

Serial brain ¹⁸FDG-PET in anti-AMPA receptor limbic encephalitis.

Performance of FLT-PET for pulmonary lesion diagnosis compared with traditional FDG-PET: A meta-analysis.

Performance of 18F-FET-PET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: inherent bias in meta-analysis not revealed by quality metrics.

Practical utility of amyloid and FDG-PET in an academic dementia center.

CT for Diagnosis of Hibernoma.

CT in the diagnosis and staging of extramammary Paget's disease.

CT and CT in the Diagnosis of Indeterminate Adrenal Masses.

FDG-PET and amyloid-PET imaging: the diverging paths.

MRI.