989 Journal of Alzheimer’s Disease 52 (2016) 989–997 DOI 10.3233/JAD-151000 IOS Press Severe Brain Metabolic Decreases Associated with REM Sleep Behavior Disorder in Dementia with Lewy Bodies Leonardo Iaccarinoa,1 , Sara Marellib,c,1 , Sandro Iannacconed , Giuseppe Magnanie , Luigi Ferini-Strambib,c,∗ and Daniela Perania,c,f,g,h a Vita-Salute San Raffaele University and Division of Neuroscience, San Raffaele Scientiﬁc Institute, Milan, Italy b Department of Clinical Neurosciences, San Raffaele Scientiﬁc Institute, Neurology, Sleep Disorders Center, Milan, Italy c Vita-Salute San Raffaele University, Faculty of Psychology, Milan, Italy d Department of Clinical Neurosciences, San Raffaele Scientiﬁc Institute, Neurorehabilitation Unit, Milan, Italy e Department of Neurology, San Raffaele Scientiﬁc Institute, Neurology, Milan, Italy f CERMAC, Vita-Salute San Raffaele University, Milan, Italy g Istituto di Bioimmagini e Fisiologia Molecolare C.N.R., Segrate, Italy h Nuclear Medicine Unit, San Raffaele Scientiﬁc Institute, Milan, Italy Handling Associate Editor: Marco Bozzali Accepted 22 February 2016 Abstract. Background/Objective: To evaluate the prevalence of REM sleep behavior disorder (RBD) in a sample of Dementia with Lewy Bodies (DLB) and Alzheimer’s Disease (AD) patients and compare the patterns of brain glucose metabolism in DLB patients with or without the sleep disturbances. Methods: In this retrospective study, the presence of probable RBD was ascertained for 27 clinically diagnosed DLB patients and 11 AD patients by a self-administered RBD Single-Question Screen (RBD1Q), followed by a sleep structured interview by experts in sleep disorders blinded to clinical information. For 18 F-FDG-PET metabolic comparisons, we considered an additional 13 DLB patients with negative history for sleep disturbance. We performed DLB within-group comparisons covarying for age and disease duration. Results: The RBD1Q questionnaire identified 20 out of 27 DLB RBD+ and 7 out of 27 DLB RBD–. None of the AD patients was positive to RBD1Q test. 18 F-FDG-PET hypometabolism at the single- and group-level tested by means of an optimized SPM approach revealed the typical DLB metabolic pattern. Each DLB patient showed a predominant occipital hypometabolism. The SPM voxel-based comparisons revealed significant brain metabolic differences, namely a more severe metabolic decrease in DLB RBD+ in the dorsolateral and medial frontal regions, left precuneus, bilateral superior parietal lobule and rolandic operculum, and amygdala. Discussion: We found a high prevalence of RBD in DLB and none in AD, as identified by the RBD1Q questionnaire, indicating its utility in clinical practice. DLB patients with or without RBD show different hypometabolism patterns that might reflect differences in underlying pathology. Keywords: Brain metabolism, dementia, dementia with Lewy bodies, 18 F-FDG-PET, REM sleep behavior disorder, sleep 1 These authors contributed equally to this work. to: Luigi Ferini-Strambi, MD, PhD, Director, Sleep Disorders Center, University Vita-Salute San Raffaele, Via Stamira D’Ancona, 20, 20127 Milan, Italy; Full Professor ∗ Correspondence of Neurology, Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy. Tel.: +39 02 2643 3363; Fax: +39 02 2643 3394; E-mail: email@example.com. ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved 990 L. Iaccarino et al. / PET in DLB with and without RBD INTRODUCTION Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia with an incidence of 3.5/100.000 persons each year . It is characterized by parkinsonian syndrome, cognitive impairments and sleep disorders, variably associated at onset, frequently accompanied by hallucinations, fluctuations in alertness, and autonomic failures . Functional loss is also typical of the syndrome, differentially related to motor and cognitive dysfunctions . Neuroimaging with Positron Emission Tomography (PET) and Single-Photon Emission Tomography (SPECT) is considered supportive for diagnosis . 18 F-FDG-PET can detect specific patterns of brain hypometabolism involving particularly the occipital cortex, whereas DAT-SCAN can prove a loss of Dopaminergic Transporters Activity (DAT) in the basal ganglia. REM sleep behavior disorder (RBD) is a parasomnia characterized by a loss of normal muscle atonia and by complex motor activity during REM sleep, usually associated with dream mentation . RBD can occur in the absence of any other obvious associated neurologic disorder or in association with a neurodegenerative disease, in which case it is considered as symptomatic RBD. RBD is frequently associated with Parkinson’s disease (PD) [5–7], DLB , and Multiple System Atrophy (MSA) [9, 10]. In several cases it may even antedate the occurrence of motor symptoms by decades . Polysomnography (PSG) confirmation of RBD is essential to make the diagnosis of definite RBD, but when PSG confirmation of RBD is not feasible in all cases and by investigators who are not able to perform sleep studies, it is possible to make the diagnosis of clinically probable RBD or probable RBD (pRBD) [12, 13]. Aims of this study were: (i) to evaluate the presence of pRBD in a sample of DLB patients with an ad hoc RBD questionnaire (RBD1Q)  testing also for its sensitivity in distinguishing DLB from AD cases in early phase, and (ii) to assess the patterns of brain glucose hypometabolism using 18 F-FDG-PET in DLB patients, with and without sleep disturbances. (mean age ± std: 72.40 ± 7.87) and 11 AD patients (66.54 ± 8.02) fulfilled the respective criteria for clinical diagnosis [2, 15]. To limit possible artifacts due to different sample sizes in the 18 F-FDG-PET metabolic comparison between DLB patients with and without RBD, we considered an additional set of patients (N = 13) with a clinical diagnosis of DLB , and a negative history for sleep disturbances as ascertained by close relative (when possible with partners). A total of 20 DLB RBD+ patients were thus compared to 20 DLB RBD– patients (of which 7 RBDwere part of the questionnaire assessment). All the patients were admitted at the Department of Neurology, San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy. Informed written consent was obtained for all the patients. The protocol was approved by the San Raffaele Hospital Local Ethical Committee. Descriptive statistics and offline analysis were performed with SPSS software (http:// www.ibm.com/spss, v.20). Demographic summary is available in Table 1. REM sleep behavior disorder assessment The presence of pRBD was ascertained by a self-administered RBD Single-Question Screen (RBD1Q) , followed by a sleep-structured interview by experts in sleep disorders (LFS, SM), in the presence of bed partner. The RBD1Q consists of a single question, answered “yes” or “no,” as follows: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?”. This question has been validated in several languages (French, German, Japanese, Italian, Spanish, Czech, and Danish) by native-speaking medical translators or by RBD expert investigators fluent in English and the local language . Structured interview and RBD1Q data were available for all the patients. Interviewers were blinded to clinical information at the sleep interview and RBD1Q administration time. 18 F-FDG-PET functional imaging METHODS Subjects With regards to the RBD1Q evaluation, we included 38 patients of which 27 DLB patients Acquisition All subjects underwent an 18 F-FDG-PET imaging scan, using a multi-ring General Electric Discovery STE PET/CT at the Nuclear Medicine Unit, San Raffaele Hospital, Milan, Italy, following a standard L. Iaccarino et al. / PET in DLB with and without RBD 991 Table 1 Demographic and CSF measurements summary of the studied cohort Sample Size Gender (M/F) Agea Years of Education MMSE Disease Duration (Cognitive)b,c Disease Duration (RBD) Patients w/Visual Hallucinations: n (%) Patients w/Parkinsonism: n (%) CSF A␤d,e CSF T-taud,f CSF P-taud,g DLB RBD+ DLB RBD– AD RBD– 20 16/4 73 ± 6.72 9.25 ± 4.91 17.72 ± 5.66 2.82 ± 1.46 3.78 ± 3.14 10 (50%) 18 (90%) 485.71 ± 208.17 318.71 ± 248.58 64.50 ± 36.36 20 11/9 71.80 ± 9.02 9.88 ± 3.81 20.82 ± 6.07 1.43 ± 1.06 – 7 (35%) 18(90%) 420.70 ± 129.02 279.00 ± 125.61 55.20 ± 25.02 11 5/6 66.54 ± 8.02 8.27 ± 3.95 20.87 ± 4.31 3.43 ± 1.51 – – – 318.80 ± 76.01 606.50 ± 314.95 98.20 ± 47.83 Variables are expressed as mean ± std.dev, factors are expressed as frequency (%). a Marks significance in DLB versus AD group comparison (p = 0.022). b Marks significance in DLB RBD+ versus DLB RBD– group comparison (p = 0.002). c Marks significance in DLB versus AD group comparison (p = 0.015). d Available for 24/40 DLB and for 10/11 AD. e Marks significance in DLB versus AD group comparison (p = 0.010). f Marks significance in DLB versus AD group comparison (p = 0.002). g Marks significance in DLB versus AD group comparison (p = 0.013). clinical acquisition protocol described elsewhere in detail . Preprocessing Image preprocessing was carried out with SPM5 software (Wellcome Department of Imaging Neuroscience, London, UK; http://www.fil.ion. ucl.ac.uk/spm) on MATLAB 8 (MathWorksInc, Sherborn, Mass). Images were first spatially normalized using a custom optimized 18 F-FDG “dementiaspecific” template  and then underwent a Gaussian Kernel smoothing (FWHM: 8 mm) prior statistical comparisons. Single-subject and group analysis Normalized and smoothed 18 F-FDG-PET images in each patient were voxel-wisely compared to a large validated normal controls database as previously reported . Briefly, a two-sample t-test design, implemented in SPM, was adopted to evaluate wholebrain hypometabolism at individual level, entering age as a nuisance variable. Cerebral global mean computation (CGM) and proportional scaling (PS) were used to remove global variation in PET intensities. Family-Wise Error (FWE) correction for multiple comparisons at pFWE < 0.05 threshold was adopted, limiting the minimum significant cluster size to k = 100. This study design and significance was used also to verify the DLB pattern of hypometabolism at the group-level. Two experts in neuroimaging and two experts in sleep disorders checked the SPM-t maps at the individual level and the clinical records, respectively. A cross-check comparison was performed afterwards to identify the DLB cases with SPM typical hypometabolism pattern positive or negative for history of sleep disturbances or to the RBD1Q questionnaire. 18 F-FDG-PET comparison between DLB RBD+ and DLB RBD– groups We sought to investigate the brain metabolic differences in DLB patients with or without sleep disturbances by mean of group comparisons. 1. These were first run with a 1st level two-sample t-test implemented in SPM5 software, comparing directly DLB RBD+ and DLB RBD– patients 18 F-FDG-PET images and taking into account age and disease duration (as reported duration of cognitive deficits prior hospital admittance, CDO), with CGM computation and proportional scaling. 2. An additional 2nd level analysis with a twosample t-test was also run, comparing the DLB RBD+ and DLB RBD– patients individual contrast images delivered by the SPM singlesubject analysis. Age and disease duration were taken into account. For both the above analyses, statistical significance was set to p < 0.025 with a minimum cluster size of k = 100, not corrected for multiple comparisons. 3. To further examine the difference between presence of sleep disturbances and metabolic changes, we also assessed separately DLB RBD+ and DLB RBD– group-level hypome- 992 L. Iaccarino et al. / PET in DLB with and without RBD tabolism in comparison to the normal database, taking into account age differences, with CGM computation and proportional scaling. Statistical significance was set to p < 0.05 FWEcorrected for multiple comparisons with a minimum cluster size of k = 100. CSF assessment Cerebrospinal fluid (CSF) measurements for amyloid-␤ (A␤), total-tau, and phospho-tau were also evaluated, considering published pathological cut-off values to assess biomarker positivity , namely (i) A␤42 <500 ng/L for amyloid, (ii) t-tau >350 ng/L for total-tau, and (iii) p-tau >61 ng/L for phospho-tau. RESULTS Fig. 1. Differences between time from RBD and from cognitive symptoms onset in DLB RBD+ patients. Barplot showing the differences between the time (years) from cognitive deficits onset and from sleep disorder onset in the DLB RBD+ patients. Red indicates RBD duration whereas blue indicates cognitive deficits duration. REM sleep behavior disorder assessment The RBD1Q questionnaire identified 20/27 DLB RBD+ and 7/27 DLB RBD–. None of the AD patients was positive to the RBD1Q test, therefore leading to high discrimination abilities of the questionnaire for diagnosis of pRBD (1.00 specificity, 0.74 sensitivity, and 0.82 accuracy). Within-group demographic comparisons With regards to DLB patients, RBD1Q positivity was not associated with statistically significant demographic differences except for the CDO, which was significantly higher in DLB RBD+ patients (MannWhitney non-parametric independent samples test p = 0.002) (see Table 1 for details). As a further evaluation, we compared in the DLB RBD+ patients the CDO and the time from onset of sleep disorders (SDO). The medians of the two distributions were similar (CDO 3 yrs, SDO 2.87 yrs) and the nonparametric Wilcoxon signed rank test for matched pairs was not statistically significant (p = 0.507). More in detail, the slight majority (11/20, 55%) of the DLB RBD+ patients showed cognitive symptoms before RBD onset (see Fig. 1). 18 F-FDG-PET functional imaging Brain hypometabolism in single-subject and group analysis Each DLB patient showed at 18 F-FDG-PET SPM map brain posterior hypometabolism, involving temporo-parietal and occipital associative cortices, reported in literature as the metabolic hallmark of the disease, supporting diagnosis . In addition, some patients also showed clusters of reduced metabolism in dorsolateral prefrontal cortex. The same hypometabolism pattern was confirmed at the group level (see Fig. 2). 18 F-FDG-PET comparison between DLB RBD+ and DLB RBD– groups The first and second level analyses consistently revealed a more severe metabolic decrease in the DLB RBD+ with respect to DLB RBD– patients, in the dorsolateral and medial frontal regions, left precuneus, bilateral superior parietal lobule and rolandic operculum, and amygdala (pUNCORRECTED < 0.025). These differences were not related to age or disease duration (see Fig. 3). In addition, the separate comparisons between the DLB RBD+ and DLB RBD– group-level hypometabolism and normal database revealed a more extensive involvement in posterior brain regions in the DLB RBD+ group (see Supplementary Figure 1). CSF assessment CSF measurements were available for 34 patients: 14 DLB RBD+, 10 DLB RBD–, and 10 AD. We found significant differences among A␤, totaltau, and phospho-tau CSF levels in AD compared to DLB patients (Mann-Whitney non-parametric independent samples test: p = 0.010, p = 0.002, and p = 0.013, respectively; see Table 1). In the whole L. Iaccarino et al. / PET in DLB with and without RBD 993 Fig. 2. 18 F-FDG-PET SPM at the whole group level. Image showing hypometabolism in the whole DLB cohort. SPM thresholded map (pFWE < 0.05, minimum cluster size k = 100) is (left) overlaid on multiple axial planes of a standard T1 anatomical template and (right) rendered on a 3D template. Colors index magnitude of hypometabolism. See text for details. Fig. 3. Brain metabolic decrease in DLB RBD+ versus DLB RBD– groups. Images showing more severe hypometabolism in DLB RBD+ group, revealed by (A) 1st level and (B) 2nd level analyses. Statistical significance was set at p < 0.025 uncorrected, minimum cluster extent k = 100. Both the comparisons are corrected for age and disease duration. SPM maps are overlaid on multiple axial planes of a standard T1 anatomical template. See text for details. 994 L. Iaccarino et al. / PET in DLB with and without RBD DLB group, ∼71% of the patients (n = 17/24) were amyloid positive. Of these 17, 4 patients were also positive for pathological total-tau and phospho-tau levels. As for comparisons between DLB RBD+ and DLB RBD– patients, there were no significant differences (A␤ p = 0.437, total-tau p = 0.709, and phospho-tau p = 0.796, Mann-Whitney U test). Eight DLB RBD– patients (80%) were amyloid positive, and three of them were also positive for total-Tau and phophos-Tau. Within the DLB RBD+ group, 64% (n = 9/14) of the patients were amyloid positive and only one patient was also positive for total-Tau and phospho-Tau. DISCUSSION This 18 F-FDG-PET imaging study in DLB, using a voxel-based SPM approach at single-subject level, showed the specific and typical DLB brain metabolic pattern in each individual DLB patient. A number of studies in literature have reported brain glucose hypometabolism in DLB, highlighting the specific occipital pattern that is considered supportive for clinical diagnosis in the currently adopted criteria . In the present study, by using an optimized 18 F-FDG-PET SPM analysis, we confirmed the pattern of predominant occipital hypometabolism in each DLB case, which extended to parietal, temporal and dorsolateral prefrontal cortex, possibly following long-distance occipito-frontal deafferentations and alpha-synuclein spreading. With regards to the evaluation of RBD1Q and the comparisons between the AD and DLB dementia groups, 74% of the evaluated DLB patients but none of the AD patients were affected by pRBD. This is coherent with the rarity of RBD in AD-pathology and its frequent occurrence in synucleinopathy conditions , witnessed by its inclusion among the current DLB diagnostic criteria . It has been suggested that RBD1Q could be used for the assessment of RBD prevalence in broad-scale epidemiologic surveys of disease . Our study seems to indicate that RBD1Q may also be useful in the clinical practice in the evaluation of demented subjects. It is of note that some patients (n = 5) had a very long history of RBD symptoms (up to 10 years) with only a more recent manifestation of cognitive impairments (2–3 years history) (see Fig. 1). Therefore, these subjects first had an idiopathic RBD (iRBD) presentation and then after several years developed cognitive deficits, progressing to a DLB diagnosis. A recent obser- vational cohort study with postmortem assessment reported in 44 iRBD patients the development of DLB (n = 14), PD (n = 16), MSA (n = 1), mild cognitive impairment (MCI) (n = 5) within a median of 12 years (range 3–23) between estimated RBD onset and final diagnosis . This predementia phase in alpha-synuclein pathology is characterized by iRBD that has been shown to begin even 50 years before the appearance of the other motor and/or cognitive symptoms . Notably, in our sample, the majority of the DLB RBD+ patients (11/20, 55%) showed cognitive symptoms before RBD onset. It is known that DLB patients might show no RBD before development of dementia . Moreover, a diagnostic delay of RBD (8.7 ± 11 years) has been reported in relation to mild or infrequent occurrence of sleep behavior . DLB RBD+ patients presented a CDO (reported duration of cognitive deficits prior hospital admittance) significantly longer than DLB RBD- patients, despite a comparable Mini-Mental State Examination score (see Table 1). This result seems to suggest that, for DLB RBD- patients, it takes a shorter time to reach a significant degree of cognitive decline, while it takes longer for DLB patients with RBD. This is consistent with the hypothesis by , suggesting that these two clinical phenotypes might reflect two different underlying pathologies. In particular, DLB RBDpatients are more likely to bear a mixed AD-DLB pathology, thus possibly leading to a faster cognitive decline. To the best of our knowledge, there is no evidence in literature on metabolic differences in DLB patients with and without sleep disturbances. Here, we showed that significant differences in the amount of brain glucose metabolism may occur. The DLB RBD+ with respect to DLB RBD– patients showed a more severe metabolic decrease in the posterior typically affected cerebral regions and particularly in the bilateral superior parietal lobule and rolandic operculum, and in the left precuneus, and in addition in the dorsolateral and medial frontal regions and amygdala. These results survived the statistical corrections for age and disease duration. The amygdala is known for its involvement in synucleinopathies [25, 26]. A previous study found a significant negative association between Lewy bodies burden and amygdala volume , while this relationship was only trending toward significance in another study . The present findings consistently show a more severe hypometabolism in DLB RBD positive patients, who are expected to carry a more “pure” synuclein pathology . L. Iaccarino et al. / PET in DLB with and without RBD With regards to the metabolic involvement of posterior parietal and frontal regions, given their role in dorsal and ventral visual streams and their relation with presence of visual hallucinations in DLB [29, 30], we also assessed whether visual hallucinations were differentially present within the DLB RBD+ and DLB RBD– groups. The DLB RBD+ patients had a slightly higher frequency of concomitant visual hallucinations (50%, 10/20) with respect to the DLB RBD– group (35%, 7/20). This difference, however, was not significant (Fisher’s Exact test, p = 0.523). Therefore, in the present findings, visual hallucinations represent a limited factor. Further studies on a larger dataset will be necessary to shed more light on this crucial aspect. The brain metabolic differences we found between DLB RBD+ and RBD– groups might also reflect different patterns of both underlying pathologies and of the associated neurotransmission alterations. Consistently, in a previous study, Kotagal and co-workers reported PD RBD+ patients with a more severe neocortical, limbic, and thalamic cholinergic denervation with respect to the PD RBD– as measured in vivo with 11 C-DTBZ . The authors concluded that the presence of RBD symptoms might index a degeneration of the cholinergic system . Given the common neuropathology (alpha-synuclein accumulation) in DLB and PD [32, 33], we speculate that the present 18 F-FDG-PET findings might indicate a more severe alteration of the cholinergic system in DLB with RBD. Previous studies investigated the differences in white- and gray-matter abnormalities between early PD patients with or without RBD [34, 35]. With regards to brain atrophy, there were some structural differences, namely greater degeneration in early PD with RBD in several cerebral regions. A postmortem study in AD and DLB cases showed that in autopsy-confirmed cases with and without RBD, there were variable atrophy patterns . The RBD negative cases presented more severe atrophy in AD-signature regions, and a higher Braak neurofibrillary tangle stage. The pathologic probability of clinical DLB was, however, higher in the RBD positive group, as well as the higher frequency of parkinsonism and visual hallucinations. Therefore, different studied cohorts reported variable findings at difference to the present study where all the RBD positive and negative patients had a clinical diagnosis of probable DLB and comparable frequency of parkinsonism and visual hallucinations (see Table 1). The present findings show higher CSF amyloid in DLB RBD+ patients when compared to DLB RBD– patients, even if this difference was not statistically 995 significant (p = 0.437 Mann-Whitney U test). These findings may still indicate that DLB RBD+ patients may present with a more “pure” synuclein-driven pathology, with respect to a greater concomitant Alzheimer pathology in DLB RBD– patients . On the basis of the neuropathological differences found between DLB RBD+ and DLB RBD– patients, some authors have suggested different DLB subtypes . Future neuroimaging studies in DLB larger samples, with or without RBD, measuring either amyloid- or tau-burden and neurodegeneration (18 F-FDG-PET) might be of utmost interest for the identification of possible DLB subtypes. A limitation of our study is the lack of PSG evaluation. However, other recent studies enrolled patients with the diagnosis of “pRBD” in absence of PSG study [28, 34, 36, 37]. Some studies reported that clinical characteristics differ between PD with and without RBD [38, 39]. Our study also shows that 18 F-FDG-PET findings differ between DLB with and without RBD. As recently suggested for PD patients , the identification of different subtypes of neurodegenerative disorders also in relation to the presence of RBD, could be of fundamental importance for potential neuroprotective intervention with disease-modifying therapy. DISCLOSURE STATEMENT Authors’ disclosures available online (http://jalz.com/manuscript-disclosures/15-1000r1). SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/ 10.3233/JAD-151000. REFERENCES   Savica R, Grossardt BR, Bower JH, Boeve BF, Ahlskog JE, Rocca WA (2013) Incidence of Dementia With Lewy Bodies and Parkinson Disease Dementia. JAMA Neurol 70, 1396-1402. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, 996              L. Iaccarino et al. / PET in DLB with and without RBD Yamada M (2005) Consortium on DLB Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology 65, 1863-1872. Hamilton JM, Salmon DP, Raman R, Hansen LA, Masliah E, Peavy GM, Galasko D (2014) Accounting for functional loss in Alzheimer’s disease and dementia with Lewy bodies: Beyond cognition. Alzheimers Dement 10, 171-178. Mahowald MW, Schenck CH (2011) REM sleep parasomnias. In Principles and Practice of Sleep Medicine, 5the ed., Kryger MH, Roth T, Dement C, eds. Elsevier Saunders, Philadelphia, pp. 1083-1097. Comella CL, Nardine TM, Diederich NJ, Stebbins GT (1998) Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 51, 526-529. Adler CH, Hentz JG, Shill HA, Sabbagh MN, DriverDunckley E, Evidente VG, Jacobson SA, Beach TG, Boeve B, Caviness JN (2011) Probable RBD is increased in Parkinson’s disease but not in essential tremor or restless legs syndrome. Parkinsonism Relat Disord 17, 456-458. Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol 12, 469-482. Boeve BF, Silber MH, Ferman TJ, Kokmen E, Smith GE, Ivnik RJ, Parisi JE, Olson EJ, Petersen RC (1998) REM sleep behavior disorder and degenerative dementia An association likely reflecting Lewy body disease. Neurology 51, 363-370. Plazzi G, Corsini R, Provini F, Pierangeli G, Martinelli P, Montagna P, Lugaresi E, Cortelli P (1997) REM sleep behavior disorders in multiple system atrophy. Neurology 48, 1094-1096. Tachibana N, Kimura K, Kitajima K, Shinde A, Kimura J, Shibasaki H (1997) REM sleep motor dysfunction in multiple system atrophy: With special emphasis on sleep talk as its early clinical manifestation. J Neurol Neurosurg Psychiatry 63, 678-681. Ferini-Strambi L, Marelli S, Galbiati A, Rinaldi F, Giora E (2014) REM sleep behavior disorder (RBD) as a marker of neurodegenerative disorders. Arch Ital Biol 152, 129-146. Boeve BF (2010) REM sleep behavior disorder. Ann N Y Acad Sci 1184, 15-54. Frauscher B, Högl B (2015) Quality control for diagnosis of REM sleep behavior disorder: Criteria, questionnaires, video, and polysomnography. In Disorders of Sleep and Circadian Rhythms in Parkinson’s Disease, Videnovic A, Högl B, eds. Springer, Vienna, pp. 145-157. Postuma RB, Arnulf I, Hogl B, Iranzo A, Miyamoto T, Dauvilliers Y, Oertel W, Ju YE, Puligheddu M, Jennum P, Pelletier A, Wolfson C, Leu-Semenescu S, Frauscher B, Miyamoto M, Cochen De Cock V, Unger MM, Stiasny-Kolster K, Fantini ML, Montplaisir JY (2012) A single-question screen for rapid eye movement sleep behaviour disorder: A multicenter validation study. Mov Disord 27, 913-916. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263-269.               Perani D, Della Rosa PA, Cerami C, Gallivanone F, Fallanca F, Vanoli EG, Panzacchi A, Nobili F, Pappatà S, Marcone A, Garibotto V, Castiglioni I, Magnani G, Cappa SF, Gianolli L, Consortium EADC-PET (2014) Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting. Neuroimage Clin 6, 445-454. Della Rosa PA, Cerami C, Gallivanone F, Prestia A, Caroli A, Castiglioni I, Gilardi MC, Frisoni G, Friston K, Ashburner J, Perani D, Consortium EADC-PET (2014) A standardized [18F]-FDG-PET template for spatial normalization in statistical parametric mapping of dementia. Neuroinformatics 12, 575-593. Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttilä T (2009) Cerebrospinal fluid beta-amyloid 42 and tau proteins as biomarkers of Alzheimer- type pathologic changes in the brain. Arch Neurol 66, 382-389. Boeve BF, Silber MH, Parisi JE, Dickson DW, Ferman TJ, Benarroch EE, Schmeichel AM, Smith GE, Petersen RC, Ahlskog JE, Matsumoto JY, Knopman DS, Schenck CH, Mahowald MW (2003) Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61, 40-45. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle R, Vilaseca I, Lomeña F, Vilas D, Lladó A, Gaig C, Santamaria J (2013) Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: An observational cohort study. Lancet Neurol 12, 443-453. Claassen DO, Josephs KA, Ahlskog JE, Silber MH, Tippmann-Peikert M, Boeve BF (2010) REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 75, 494-499. Fujishiro H, Nakamura S, Sato K, Iseki E (2015) Prodromal dementia with Lewy bodies. Geriatr Gerontol Int 15, 817826. White C, Hill EA, Morrison I, Riha RL (2012) Diagnostic delay in REM sleep behavior disorder (RBD). J Clin Sleep Med 8, 133-136. Dugger BN, Boeve BF, Murray ME, Parisi JE, Fujishiro H, Dickson DW, Ferman TJ (2012) Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies. Mov Disord 27, 72-78. Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J, Jellinger K (1994) Amygdala pathology in Parkinson’s disease. Acta Neuropathol 88, 493-500. Halliday GM, Holton JL, Revesz T, Dickson DW (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122, 187-204. Burton EJ, Mukaetova-Ladinska EB, Perry RH, Jaros E, Barber R, O’Brien JT (2012) Neuropathological correlates of volumetric MRI in autopsy-confirmed Lewy body dementia. Neurobiol Aging 33, 1228-1236. Murray ME, Ferman TJ, Boeve BF, Przybelski SA, Lesnick TG, Liesinger AM, Senjem ML, Gunter JL, Preboske GM, Lowe VJ, Vemuri P, Dugger BN, Knopman DS, Smith GE, Parisi JE, Silber MH, Graff-Radford NR, Petersen RC, Jack CR Jr, Dickson DW, Kantarci K (2013) MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies. Neurology 81, 1681-1689. Perneczky R, Drzezga A, Boecker H, Wagenpfeil S, Förstl H, Kurz A, Häussermann P (2009) Right prefrontal hypometabolism predicts delusions in dementia with Lewy bodies. Neurobiol Aging 30, 1420-1429. L. Iaccarino et al. / PET in DLB with and without RBD      Sanchez-Castaneda C, Rene R, Ramirez-Ruiz B, Campdelacreu J, Gascon J, Falcon C, Calopa M, Jauma S, Juncadella M, Junque C (2010) Frontal and associative visual areas related to visual hallucinations in dementia with Lewy bodies and Parkinson’s disease with dementia. Mov Disord 25, 615-622. Kotagal V, Albin RL, Müller MLTM, Koeppe RA, Chervin RD, Frey KA, Bohnen NI (2012) Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann Neurol 71, 560-568. Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK (2007) DLB/PDD Working Group. DLB and PDD boundary issues Diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68, 812-819. Goedert M, Spillantini MG, Del Tredici K, Braak H (2012) 100 years of Lewy pathology. Nat Rev Neurol 9, 13-24. Ford AH, Duncan GW, Firbank MJ, Yarnall AJ, Khoo TK, Burn DJ, O’Brien JT (2013) Rapid eye movement sleep behavior disorder in Parkinson’s disease: Magnetic resonance imaging study. Mov Disord 28, 832-836.       997 Lim J-S, Shin SA, Lee J-Y, Nam H, Lee J-Y, Kim YK (2016) Neural substrates of rapid eye movement sleep behavior disorder in Parkinson’s disease. Parkinsonism Relat Disord 23, 31-36. Postuma RB, Adler CH, Dugger BN, Hentz JG, Shill HA, Driver-Dunckley E, Sabbagh MN, Jacobson SA, Belden CM, Sue LI, Serrano G, Beach TG (2015) REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov Disord 30, 1413-1417. Mahlknecht P, Seppi K, Frauscher B, Kiechl S, Willeit J, Stockner H, Djamshidian A, Nocker M, Rastner V, Defrancesco M, Rungger G, Gasperi A, Poewe W, Högl B (2015) Probable RBD and association with neurodegenerative disease markers: A population-based study. Mov Disord 30, 1417-1421. Nomura T, Inoue Y, Kagimura T, Nakashima K (2013) Clinical significance of REM sleep behavior disorder in Parkinson’s disease. Sleep Med 14, 131-135. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY (2009) Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson’s disease. Brain 132, 3298-3307. Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB (2015) New clinical subtypes of Parkinson disease and their longitudinal progression: A prospective cohort comparison with other phenotypes. JAMA Neurol 72, 863-873.