Psychiatry and Clinical Neurosciences 2014; 68: 137–144
doi:10.1111/pcn.12101
Regular Article
Primary visual cortical metabolism and rapid eye movement sleep behavior disorder in dementia with Lewy bodies Yuhei Chiba, MD,1,2,4 Eizo Iseki, MD, PhD,1,2 Hiroshige Fujishiro, MD, PhD,1,2* Kazumi Ota, MA,1 Koji Kasanuki, MD, PhD,1,2 Heii Arai, MD, PhD,3 Yoshio Hirayasu, MD, PhD4 and Kiyoshi Sato, MD, PhD1 1
PET/CT Dementia Research Center, 2Department of Psychiatry, Juntendo Tokyo Koto Geriatric Medical Center, Department of Psychiatry, Juntendo University School of Medicine, Tokyo and 4Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan 3
Aim: Significant glucose hypometabolism in the primary visual cortex (PVC) is considered to support a diagnosis of dementia with Lewy bodies (DLB), but its relationship to the clinical features remains unknown. The purpose of this study was to assess the association between the metabolic pattern and clinical variables in DLB. Methods: A total of 27 DLB patients who underwent [18F]fluoro-d-glucose (18F-FDG) positron emission tomography scans were examined. Demographics and clinical variables were compared between patients with and without glucose hypometabolism in the PVC. The correlations between the cerebral metabolic rate of glucose in the PVC and clinical variables were also investigated. Results: Only the onset age of probable rapid eye movement sleep behavior disorder (RBD) was significantly different between patients with and without
EMENTIA WITH LEWY BODIES (DLB) is defined pathologically as degeneration in the central, peripheral, and autonomic nervous system associated with Lewy bodies (LB). DLB is clinically characterized by progressive dementia, which is frequently accompanied by parkinsonism and visual
D
*Correspondence: Hiroshige Fujishiro, MD, PhD, PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan. Email: [email protected] Received 7 November 2012; revised 17 May 2013; accepted 3 August 2013.
glucose hypometabolism in the PVC, being younger in patients with the metabolic pattern; there were no other differences in clinical variables. The onset age of probable RBD was significantly correlated with the cerebral metabolic rate of glucose in the PVC.
Conclusions: Glucose hypometabolism in the PVC provides a potential mechanism for the link between antecedent RBD and the subsequent development of dementia in DLB patients. Glucose hypometabolism in the PVC may represent the effect of the pathophysiological process of DLB on RBD rather than a distinct condition in the disease progression. The physiological aspects of the link between this metabolic pattern and the onset of RBD remain unclear. Key words: [18F]-FDG PET, dementia with Lewy bodies, pathology, rapid eye movement sleep behavior disorder.
hallucinations.1 Recent studies have revealed that autonomic dysfunction, olfactory dysfunction, and rapid eye movement sleep behavior disorder (RBD) antedate the onset of dementia by years or even decades, suggesting diversity in clinical courses and the long-term nature of the disease.2–4 Significant hypometabolism in the occipital cortex on [18F]fluoro-d-glucose (18F-FDG) positron emission tomography (PET) scans, particularly in the primary visual cortex (PVC), is considered to support a diagnosis of DLB.5 Only a subset of patients with DLB, however, exhibit glucose hypometabolism in the PVC in clinical practice, and the relevance of occipital
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
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metabolic reduction to clinical features remains unknown. Minoshima et al. have reported that MiniMental State Examination (MMSE) scores in patients with DLB are uncorrelated with metabolic reduction in the visual cortex and occipital association cortex,5 and that hypometabolism in those regions is independent of disease progression. We recently reported that some patients with glucose hypometabolism in the PVC who exhibit no dementia nevertheless exhibit certain other clinical features of DLB, mainly probable RBD, which can be considered one of the prodromal states of DLB.6 Given that metabolic reduction in the PVC is independent of the associated clinical condition, identifying the onset ages of the clinical symptoms, which could form patterns associated with each of several DLB clinical courses, might clarify what the metabolic reduction in the PVC represents. In the present study, we compared the clinical variables of DLB patients with and without glucose hypometabolism in the PVC. We also investigated DLB patients, focusing in particular on the onset ages of clinical symptoms. The purpose of this study was to investigate the association between metabolic reduction in the PVC and clinical features, including the prodromal phase before the onset of dementia.
movements occurring during sleep that are potentially injurious to the patient and bed partner, which are consistent with the proposed diagnostic criteria for probable RBD.7 The presence or absence of visual hallucination was obtained from the patient and his or her informant. The score on the motor component of the Unified Parkinson’s Disease Rating Scale (UPDRS) was also recorded as an indicator of the severity of parkinsonism. Motor manifestations were considered to be tremor dominant if the summed limb UPDRS tremor scores were ≥4 (items 20 and 21), with at least one limb scoring ≥2.8 In addition to the prevalence of these clinical symptoms, the onset age of each symptom was also obtained to assess the prodromal phase that occurs before the onset of dementia. The MMSE, the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale-III (WAIS-III), and the Bender Gestalt Test (BGT) were used to assess cognitive ability. Brain atrophy in the head MRI was evaluated by Scheltens’ Medial Temporal Lobe Atrophy scale 0–4.9 Periventricular hyperintensity (PVH), and deep and subcortical white matter hyperintensity (DSWMH) were evaluated by Fazekas’ scale (range 0–3) based on T2-weighted MRI examination.10 No patients scored higher than 3 on the Fazekas’ scale on T2-weighted magnetic resonance imaging in this study. In 20 of 27 patients with DLB, cardiac [123I]-metaiodobenzylguanidine (MIBG) scintigraphy was also performed to determine whether underlying Lewy body disease was present.11 The heart : mediastinum (H : M) ratios for early and delayed images were calculated. The findings of cardiac [123I]-MIBG scintigraphy in patients with DLB were consistent with characteristics of DLB.1,11 This study was approved by the Ethics Committee of Juntendo Tokyo Koto Geriatric Medical Center. Written informed consent was obtained from all patients or the patients’ caregivers.
METHODS Twenty-three patients with probable DLB and four patients with possible DLB were examined in the present study. All patients underwent 18F-FDG PET scans between April and November 2011 at our memory clinic, the PET/CT Dementia Research Center at the Juntendo Tokyo Koto Geriatric Medical Center. The clinical diagnosis of DLB was made according to the Third Consortium on DLB (CDLB) clinical criteria.1 The presence or absence of each clinical feature of DLB was obtained from both the patient and his or her informants. Prodromal symptoms were assessed using a standardized worksheet as previously reported.2 The worksheet included 10 specific questions regarding the non-motor symptoms of Parkinson’s disease (PD): (i) anosmia or hyposmia; (ii) constipation (>3 days); (iii) orthostatic dizziness; (iv) urinary incontinence; (v) increased sweating; (vi) increased salivation; (vii) depression; (viii) anxiety with a history of visiting a physician; (ix) moodiness; and (x) lack of motivation in the performance of daily activities (apathy). RBD is defined as wild flailing
18
F-FDG PET scan procedure and definition of hypometabolism in the primary visual cortex The [18F]-FDG PET scans were performed as previously reported.6,12 In order to evaluate regional cerebral metabolic rate of glucose (CMRglc) decrease in all patients, the CMRglc for each patient was compared using 3-D stereotactic surface projection (3D-SSP) analysis with an age-matched normative database consisting of data from 77 normal healthy volunteers between 41 and 84 years of age (36 men and 41 women).12 The difference in CMRglc between each
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
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Primary visual cortex and RBD in DLB 139
patient and this database was expressed as a Z-score (normal mean – individual value/normal SD) and superimposed onto 3D-SSP maps.13 Hypometabolism in the PVC was measured based on the average extent of CMRglc reduction in each primary visual cortex on the [18F]-FDG PET scans at a Z-score of >1.0. Significant hypometabolism in the PVC was defined as a difference greater than 40% from the average extent of CMRglc reduction as described in the previous study.6
parkinsonism, or the prevalence of tremor-dominant parkinsonism. The mean age at onset of probable RBD was significantly younger in patients with glucose hypometabolism in the PVC than in those without, whereas there were no differences in the onset ages of other examined clinical features of DLB. The correlation of the CMRglc in the PVC to clinical variables is shown in Table 3. There were no demographic or neuropsychological characteristics that correlated to the CMRglc in the PVC. Only the age at onset of probable RBD was negatively correlated to the CMRglc in the PVC. There were no correlations between onset ages of other examined clinical features of DLB and the CMRglc in the PVC.
Statistical analysis Data were analyzed using SPSS 20.0 (SPSS, Chicago, IL, USA), with the significance level set at P < 0.05. Patients with and without glucose hypometabolism in the PVC on [18F]-FDG PET scans were compared with respect to the following variables: age at evaluation, sex, age at onset of DLB, duration of education, MMSE score, WAIS-III scores, WMS-R scores, BGT score, UPDRS motor score, prevalence of tremordominant type parkinsonism, age at onset and prevalence of clinical features, and duration of probable RBD. The Student’s t-test or the Mann–Whitney sum rank test was performed as appropriate for age, duration of education, and neuropsychological test results. Fisher’s exact test or the χ2-test was performed as appropriate for sex ratio and frequency of each clinical feature. Spearman’s rank order correlation coefficient was used to evaluate correlations between the extent of the reduction in CMRglc in the PVC and variables, including age at evaluation, age at onset of DLB, duration of education, MMSE score, WAIS-III scores, WMS-R scores, BGT score, early and delayed H : M ratio of [123I]-MIBG scintigraphy, UDPRS motor score and age at onset of clinical features.
RESULTS Of 27 patients with DLB who underwent [18F]-FDGPET scans, 16 were considered to have glucose hypometabolism in the PVC. A comparison of patients with and without glucose hypometabolism in the PVC revealed no differences in demographics or neuropsychological characteristics or radiological findings (Table 1). Clinical profiles of patients with and without glucose hypometabolism in the PVC are summarized in Table 2, showing that there were no differences between the groups in the prevalence of clinical features, the duration of probable RBD, the severity of
DISCUSSION In the present study, 16 of 27 patients with DLB had glucose hypometabolism in the PVC. Patients with and without glucose hypometabolism in the PVC showed no significant differences in demographics, neuropsychological characteristics, radiological findings, the prevalence of clinical features of DLB, or the severity and characteristics of parkinsonism. Only the onset age of probable RBD was significantly younger in patients with glucose hypometabolism in the PVC, whereas there were no differences in the onset ages of other examined clinical features. Moreover, the onset age of probable RBD was significantly correlated with the CMRglc in the PVC. These results suggest that metabolic reduction in the PVC may represent the effect of the pathophysiological process of DLB on RBD rather than a distinct condition in the disease progression of DLB. In brains of patients with DLB, the density of Lewy bodies is reportedly the lowest in the occipital cortex. Hypometabolism in the PVC is thought to reflect a disturbance of the neuronal projection from another part of the brain, although it is partly caused by primary degeneration of the occipital cortex.14 Satoh et al. reported that the regional CMRglc in the medial occipital cortex, but not in the lateral occipital cortex, changed significantly 3 months after cholinesterase inhibitors were started in patients with DLB.15 Mori et al. reported that regional cerebral blood flow in the occipital cortex was increased and visual hallucination was improved in response to cholinesteraseinhibiting medication in DLB patients.16 Shimada et al. demonstrated brain acetylcholinesterase (AChE) activity in patients with Lewy body disease, including
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
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Table 1. Comparisons of demographics, neuropsychological data and clinical features between patients with and without hypometabolism in PVC
Age at evaluation (years) Age at onset of dementia (years) Male (%) Duration of education (years) MMSE score WAIS-III Full scale IQ Verbal IQ Performance IQ WMS-R General memory Verbal memory Visual memory Attention/concentration Delayed recall Bender Gestalt test MRI Scheltens’ scale Left medial temporal lobe atrophy Right medial temporal lobe atrophy MRI Fazekas’ scale PVH DSWMH [123I]-MIBG scintigraphy Early H : M ratio (%) Delayed H : M ratio (%)
With glucose hypometabolism in PVC (n = 16)
Without glucose hypometabolism in PVC (n = 11)
74.6 ± 5.3 71.6 ± 5.5 75.0% 12.1 ± 2.3 22.0 ± 4.6 n = 11 94.7 ± 19.8 102.5 ± 18.7 86.5 ± 18.5 n = 11 86.5 ± 11.5 89.0 ± 9.3 86.6 ± 16.1 99.8 ± 11.1 85.2 ± 13.4 n = 14 99.4 ± 42.0 n = 16 1 [0, 1.75] 1 [0, 1] n = 16 1 [0.25, 1.75] 1 [0, 1.75] n = 12 1.84 ± 0.33 1.40 ± 0.22
76.5 ± 5.3 73.1 ± 5.2 72.7% 12.5 ± 2.8 22.8 ± 4.8 n = 10 99.1 ± 8.0 104.5 ± 9.2 92.1 ± 8.5 n = 10 85.4 ± 9.2 90.4 ± 7.6 80.9 ± 14.6 101.7 ± 11.1 80.0 ± 10.2 n = 11 76.0 ± 28.0 n = 11 1 [0, 2] 1 [0, 2] n = 11 1 [0, 1.0] 0 [0, 2.0] n=8 1.74 ± 0.29 1.31 ± 0.18
P-value P = 0.419 P = 0.491 P = 0.502 P = 0.751 P = 0.657 P = 0.522 P = 0.768 P = 0.397 P = 0.806 P = 0.712 P = 0.405 P = 0.702 P = 0.336 P = 0.127 P = 0.865 P = 0.577 P = 0.790 P = 0.942 P = 0.465 P = 0.317
Data are presented as the mean ± standard deviation, median [25%, 75%]. [123I]-MIBG scintigraphy, [123I]-metaiodobenzylguanidine scintigraphy; DSWMH, deep and sub-cortical white matter hyperintensity; H : M ratio, heart to mediastinum ratio; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PVC, primary visual cortex; PVH, periventricular hyperintensity; WAIS-III, Wechsler Adult Intelligence Scale-III; WMS-R, Wechsler Memory Scale-Revised.
DLB.17 They revealed that brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. Even de novo early PD patients exhibited significant reductions in AChE activity in the medial occipital cortex, suggesting that brain cholinergic dysfunction may precede the manifestation of motor dysfunction in PD. These reports suggest that glucose hypometabolism in the PVC may be related to cholinergic disturbance in patients with DLB. RBD, one of the suggestive clinical features of DLB, is a type of parasomnia that is characterized by a lack of motor inhibition during rapid eye movement (REM) sleep that leads to potentially harmful dream-
enacting behaviors.7 In a longitudinally followed cohort of 234 autopsy-confirmed dementia patients, a history of definite or probable RBD was present in 76% of 98 patients with autopsy-confirmed DLB.4 In contrast, only five of 136 patients without autopsy-confirmed DLB exhibited probable RBD. REM sleep without atonia was not confirmed using polysomnography in any of the five patients. These results suggest the close relation between RBD and DLB pathology. Moreover, Dugger et al. reported that 60% of autopsy-confirmed DLB patients developed probable RBD before or during the year of estimated dementia onset,3 suggesting that RBD may be related to the onset of DLB.
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
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Table 2. Comparison of clinical features between patients with and without hypometabolism in PVC
Clinical features Parkinsonism Prevalence (%) Age at onset UPDRS motor score Prevalence of tremor dominant type Visual hallucinations Prevalence (%) Age at onset Probable RBD Prevalence (%) Age at onset Duration (years) Olfactory disturbance Prevalence (%) Age at onset Constipation Prevalence (%) Age at onset Orthostatic dizziness Prevalence (%) Age at onset Urinary incontinence Prevalence (%) Age at onset Increased sweating Prevalence (%) Age at onset Increased salivation Prevalence (%) Age at onset Depression Prevalence (%) Age at onset Anxiety Prevalence (%) Age at onset Moodiness Prevalence (%) Age at onset Lack of motivation Prevalence (%) Age at onset
With glucose hypometabolism in PVC (n = 16)
Without glucose hypometabolism in PVC (n = 11)
P-value
68.8% 74.3 ± 4.6 19.8 ± 18.9 12.5%
81.8% 74.4 ± 4.3 16.4 ± 16.9 18.2%
P = 0.383 P = 0.932 P = 0.652 P = 0.545
75.0% 73.0 ± 5.8
72.7% 73.3 ± 5.8
P = 0.617 P = 0.926
75.0% 63.3 ± 10.6 10.1 ± 11.4
81.8% 72.1 ± 8.0 5.1 ± 5.4
P = 0.528 P = 0.049* P = 0.244
62.5% 61.2 ± 17.4
60% 63.5 ± 10.1
P = 0.609 P = 0.773
50.0% 62.8 ± 15.7
72.7% 65.6 ± 8.3
P = 0.218 P = 0.677
50% 64.1 ± 23.5
40% 70.5 ± 5.3
P = 0.464 P = 0.614
50% 72.8 ± 3.1
50% 76.6 ± 6.7
P = 0.656 P = 0.183
31.3% 70.0 ± 14.2
10% 75.0 ± 0
P = 0.225 P = 0.773
31.3% 70.8 ± 6.4
50% 71.8 ± 2.4
P = 0.293 P = 0.788
43.8% 66.3 ± 14.1
60% 71.2 ± 8.2
P = 0.344 P = 0.473
50% 70.6 ± 2.6
55.6% 71.0 ± 2.9
P = 0.560 P = 0.814
56.3% 70.9 ± 3.4
40% 76.3 ± 9.5
P = 0.344 P = 0.344
56.3% 74.1 ± 3.6
70% 59.8 ± 29.5
P = 0.391 P = 0.290
Data are presented as the mean ± SD. *Statistically significant P-values (P < 0.05). PVC, primary visual cortex; RBD, rapid eye movement sleep behavior disorder; UPDRS, Unified Parkinson’s Disease Rating Scale.
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Table 3. Demographic data, psychological data and clinical features of the DLB patients, and correlation of these to hypometabolism in the PVC Correlation to hypometabolism in the PVC Demographics Age at evaluation Age at onset of dementia Duration of education Psychological tests MMSE score WAIS-III (n = 21) Full scale IQ Verbal IQ Performance IQ WMS-R (n = 21) General memory score Verbal memory score Visual memory score Attention/concentration score Delayed recall score Bender Gestalt test score (n = 26) [123I]-MIBG scintigraphy (n = 20) Early H : M ratio Delayed H : M ratio Clinical features UPDRS score Age at onset of clinical features Parkinsonism Visual hallucination Probable RBD Olfactory disturbance Constipation Orthostatic dizziness Urinary incontinence Increased sweating Increased salivation Depression Anxiety Moodiness Lack of motivation
R = −0.074; P = 0.715 R = −0.064; P = 0.751 R = −0.098; P = 0.635 R = −0.160; P = 0.424 R = −0.010; P = 0.967 R = 0.027; P = 0.908 R = −0.030; P = 0.894 R = 0.090; P = 0.701 R = −0.070; P = 0.771 R = 0.210; P = 0.356 R = −0.060; P = 0.783 R = 0.250; P = 0.279 R = 0.310; P = 0.152 R = 0.125; P = 0.598 R = 0.184; P = 0.436 R = 0.140; P = 0.493 R = 0.052; P = 0.827 R = 0.049; P = 0.837 R = −0.430; P = 0.047* R = −0.133; P = 0.623 R = −0.088; P = 0.775 R = −0.254; P = 0.451 R = −0.289; P = 0.338 R = −0.205; P = 0.740 R = −0.124; P = 0.751 R = −0.099; P = 0.726 R = −0.168; P = 0.583 R = −0.312; P = 0.299 R = 0.372; P = 0.172
*Statistically significant P-values (P < 0.05). [123I]-MIBG scintigraphy, [123I]-metaiodobenzylguanidine scintigraphy; DLB, dementia with Lewy bodies; H: M ratio; heart, mediastinum ratio; MMSE, Mini-Mental State Examination; RBD, rapid eye movement sleep behavior disorder; UPDRS, Unified Parkinson’s Disease Rating Scale; PVC, primary visual cortex; WAIS-III, Wechsler Adult Intelligence Scale-III; WMS-R, Wechsler Memory Scale-Revised.
Although there is as yet little information regarding the existence of subtypes in patients with DLB,3 evidence that RBD may be an important marker of a particular subtype of PD is rapidly accumulating.18–22 Many recent studies suggest that symptoms of RBD can predict development of dementia, visual hallucinations, and cognitive fluctuation in patients with PD.22 Moreover, RBD has been associated with non-tremor-predominant form, symmetric disease, and increased autonomic dysfunction in patients with PD.8,19,21–23 These clinical characteristics are generally compatible with those in patients with DLB. Given that the reported occurrence of RBD in PD varies from 15 to 47%,24 RBD seems to be more common in patients with DLB. In the present study, the difference in the onset age of RBD between groups with and without glucose hypometabolism in the PVC raises the possibility of the existence of subtypes in patients with DLB. Because of the relatively small sample size in this study, it is possible that differences in other clinical variables exist between the two groups but do not reach statistical significance. Further studies with larger sample sizes and more detailed clinical evaluation will be needed to confirm our hypothesis. Kotagal et al. have recently investigated the correlation between RBD and a variety of neurotransmitter deficits based on neuroimages in patients with PD.25 They revealed that the presence of RBD symptoms in PD is associated with cholinergic denervation. Moreover, AChE inhibitor was reported to improve the symptoms of RBD,26 suggesting that cholinergic degeneration may play a role in the pathogenesis of RBD. Cholinergic denervation may be one of the common modes of pathogenesis, forming the link between RBD and metabolic reductions in the PVC. RBD clearly plays an important role in the pathogenesis of DLB. We recently reported on the variability in the patterns of cortical metabolism in patients with probable RBD: a subset of non-demented patients exhibited glucose hypometabolism in the PVC even when core features of DLB were absent.27 Many recent longitudinal studies have revealed that idiopathic RBD is a much more sensitive and specific prodromal marker of DLB than any other symptom, including olfactory and autonomic dysfunctions.4,7,19,21 If we are able to elucidate the link between the occurrence of RBD and the emergence of glucose hypometabolism in the PVC, the long prodromal phase of RBD could provide a critical opportunity for potential intervention with disease-modifying therapy for DLB.
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2014; 68: 137–144
ACKNOWLEDGMENTS This study was supported in part by the Anti-Aging Research Center of Juntendo University School of Medicine, The Ogasawara Foundation for the Promotion of Science and Engineering, Nihon Medi-Physics, the 21st Novartis Foundation of Gerontological Research and the Japan Geriatrics Society (2011). The authors have no conflicts of interest.
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© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12101
Regular Article
Primary visual cortical metabolism and rapid eye movement sleep behavior disorder in dementia with Lewy bodies Yuhei Chiba, MD,1,2,4 Eizo Iseki, MD, PhD,1,2 Hiroshige Fujishiro, MD, PhD,1,2* Kazumi Ota, MA,1 Koji Kasanuki, MD, PhD,1,2 Heii Arai, MD, PhD,3 Yoshio Hirayasu, MD, PhD4 and Kiyoshi Sato, MD, PhD1 1
PET/CT Dementia Research Center, 2Department of Psychiatry, Juntendo Tokyo Koto Geriatric Medical Center, Department of Psychiatry, Juntendo University School of Medicine, Tokyo and 4Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan 3
Aim: Significant glucose hypometabolism in the primary visual cortex (PVC) is considered to support a diagnosis of dementia with Lewy bodies (DLB), but its relationship to the clinical features remains unknown. The purpose of this study was to assess the association between the metabolic pattern and clinical variables in DLB. Methods: A total of 27 DLB patients who underwent [18F]fluoro-d-glucose (18F-FDG) positron emission tomography scans were examined. Demographics and clinical variables were compared between patients with and without glucose hypometabolism in the PVC. The correlations between the cerebral metabolic rate of glucose in the PVC and clinical variables were also investigated. Results: Only the onset age of probable rapid eye movement sleep behavior disorder (RBD) was significantly different between patients with and without
EMENTIA WITH LEWY BODIES (DLB) is defined pathologically as degeneration in the central, peripheral, and autonomic nervous system associated with Lewy bodies (LB). DLB is clinically characterized by progressive dementia, which is frequently accompanied by parkinsonism and visual
D
*Correspondence: Hiroshige Fujishiro, MD, PhD, PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan. Email: [email protected] Received 7 November 2012; revised 17 May 2013; accepted 3 August 2013.
glucose hypometabolism in the PVC, being younger in patients with the metabolic pattern; there were no other differences in clinical variables. The onset age of probable RBD was significantly correlated with the cerebral metabolic rate of glucose in the PVC.
Conclusions: Glucose hypometabolism in the PVC provides a potential mechanism for the link between antecedent RBD and the subsequent development of dementia in DLB patients. Glucose hypometabolism in the PVC may represent the effect of the pathophysiological process of DLB on RBD rather than a distinct condition in the disease progression. The physiological aspects of the link between this metabolic pattern and the onset of RBD remain unclear. Key words: [18F]-FDG PET, dementia with Lewy bodies, pathology, rapid eye movement sleep behavior disorder.
hallucinations.1 Recent studies have revealed that autonomic dysfunction, olfactory dysfunction, and rapid eye movement sleep behavior disorder (RBD) antedate the onset of dementia by years or even decades, suggesting diversity in clinical courses and the long-term nature of the disease.2–4 Significant hypometabolism in the occipital cortex on [18F]fluoro-d-glucose (18F-FDG) positron emission tomography (PET) scans, particularly in the primary visual cortex (PVC), is considered to support a diagnosis of DLB.5 Only a subset of patients with DLB, however, exhibit glucose hypometabolism in the PVC in clinical practice, and the relevance of occipital
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metabolic reduction to clinical features remains unknown. Minoshima et al. have reported that MiniMental State Examination (MMSE) scores in patients with DLB are uncorrelated with metabolic reduction in the visual cortex and occipital association cortex,5 and that hypometabolism in those regions is independent of disease progression. We recently reported that some patients with glucose hypometabolism in the PVC who exhibit no dementia nevertheless exhibit certain other clinical features of DLB, mainly probable RBD, which can be considered one of the prodromal states of DLB.6 Given that metabolic reduction in the PVC is independent of the associated clinical condition, identifying the onset ages of the clinical symptoms, which could form patterns associated with each of several DLB clinical courses, might clarify what the metabolic reduction in the PVC represents. In the present study, we compared the clinical variables of DLB patients with and without glucose hypometabolism in the PVC. We also investigated DLB patients, focusing in particular on the onset ages of clinical symptoms. The purpose of this study was to investigate the association between metabolic reduction in the PVC and clinical features, including the prodromal phase before the onset of dementia.
movements occurring during sleep that are potentially injurious to the patient and bed partner, which are consistent with the proposed diagnostic criteria for probable RBD.7 The presence or absence of visual hallucination was obtained from the patient and his or her informant. The score on the motor component of the Unified Parkinson’s Disease Rating Scale (UPDRS) was also recorded as an indicator of the severity of parkinsonism. Motor manifestations were considered to be tremor dominant if the summed limb UPDRS tremor scores were ≥4 (items 20 and 21), with at least one limb scoring ≥2.8 In addition to the prevalence of these clinical symptoms, the onset age of each symptom was also obtained to assess the prodromal phase that occurs before the onset of dementia. The MMSE, the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale-III (WAIS-III), and the Bender Gestalt Test (BGT) were used to assess cognitive ability. Brain atrophy in the head MRI was evaluated by Scheltens’ Medial Temporal Lobe Atrophy scale 0–4.9 Periventricular hyperintensity (PVH), and deep and subcortical white matter hyperintensity (DSWMH) were evaluated by Fazekas’ scale (range 0–3) based on T2-weighted MRI examination.10 No patients scored higher than 3 on the Fazekas’ scale on T2-weighted magnetic resonance imaging in this study. In 20 of 27 patients with DLB, cardiac [123I]-metaiodobenzylguanidine (MIBG) scintigraphy was also performed to determine whether underlying Lewy body disease was present.11 The heart : mediastinum (H : M) ratios for early and delayed images were calculated. The findings of cardiac [123I]-MIBG scintigraphy in patients with DLB were consistent with characteristics of DLB.1,11 This study was approved by the Ethics Committee of Juntendo Tokyo Koto Geriatric Medical Center. Written informed consent was obtained from all patients or the patients’ caregivers.
METHODS Twenty-three patients with probable DLB and four patients with possible DLB were examined in the present study. All patients underwent 18F-FDG PET scans between April and November 2011 at our memory clinic, the PET/CT Dementia Research Center at the Juntendo Tokyo Koto Geriatric Medical Center. The clinical diagnosis of DLB was made according to the Third Consortium on DLB (CDLB) clinical criteria.1 The presence or absence of each clinical feature of DLB was obtained from both the patient and his or her informants. Prodromal symptoms were assessed using a standardized worksheet as previously reported.2 The worksheet included 10 specific questions regarding the non-motor symptoms of Parkinson’s disease (PD): (i) anosmia or hyposmia; (ii) constipation (>3 days); (iii) orthostatic dizziness; (iv) urinary incontinence; (v) increased sweating; (vi) increased salivation; (vii) depression; (viii) anxiety with a history of visiting a physician; (ix) moodiness; and (x) lack of motivation in the performance of daily activities (apathy). RBD is defined as wild flailing
18
F-FDG PET scan procedure and definition of hypometabolism in the primary visual cortex The [18F]-FDG PET scans were performed as previously reported.6,12 In order to evaluate regional cerebral metabolic rate of glucose (CMRglc) decrease in all patients, the CMRglc for each patient was compared using 3-D stereotactic surface projection (3D-SSP) analysis with an age-matched normative database consisting of data from 77 normal healthy volunteers between 41 and 84 years of age (36 men and 41 women).12 The difference in CMRglc between each
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patient and this database was expressed as a Z-score (normal mean – individual value/normal SD) and superimposed onto 3D-SSP maps.13 Hypometabolism in the PVC was measured based on the average extent of CMRglc reduction in each primary visual cortex on the [18F]-FDG PET scans at a Z-score of >1.0. Significant hypometabolism in the PVC was defined as a difference greater than 40% from the average extent of CMRglc reduction as described in the previous study.6
parkinsonism, or the prevalence of tremor-dominant parkinsonism. The mean age at onset of probable RBD was significantly younger in patients with glucose hypometabolism in the PVC than in those without, whereas there were no differences in the onset ages of other examined clinical features of DLB. The correlation of the CMRglc in the PVC to clinical variables is shown in Table 3. There were no demographic or neuropsychological characteristics that correlated to the CMRglc in the PVC. Only the age at onset of probable RBD was negatively correlated to the CMRglc in the PVC. There were no correlations between onset ages of other examined clinical features of DLB and the CMRglc in the PVC.
Statistical analysis Data were analyzed using SPSS 20.0 (SPSS, Chicago, IL, USA), with the significance level set at P < 0.05. Patients with and without glucose hypometabolism in the PVC on [18F]-FDG PET scans were compared with respect to the following variables: age at evaluation, sex, age at onset of DLB, duration of education, MMSE score, WAIS-III scores, WMS-R scores, BGT score, UPDRS motor score, prevalence of tremordominant type parkinsonism, age at onset and prevalence of clinical features, and duration of probable RBD. The Student’s t-test or the Mann–Whitney sum rank test was performed as appropriate for age, duration of education, and neuropsychological test results. Fisher’s exact test or the χ2-test was performed as appropriate for sex ratio and frequency of each clinical feature. Spearman’s rank order correlation coefficient was used to evaluate correlations between the extent of the reduction in CMRglc in the PVC and variables, including age at evaluation, age at onset of DLB, duration of education, MMSE score, WAIS-III scores, WMS-R scores, BGT score, early and delayed H : M ratio of [123I]-MIBG scintigraphy, UDPRS motor score and age at onset of clinical features.
RESULTS Of 27 patients with DLB who underwent [18F]-FDGPET scans, 16 were considered to have glucose hypometabolism in the PVC. A comparison of patients with and without glucose hypometabolism in the PVC revealed no differences in demographics or neuropsychological characteristics or radiological findings (Table 1). Clinical profiles of patients with and without glucose hypometabolism in the PVC are summarized in Table 2, showing that there were no differences between the groups in the prevalence of clinical features, the duration of probable RBD, the severity of
DISCUSSION In the present study, 16 of 27 patients with DLB had glucose hypometabolism in the PVC. Patients with and without glucose hypometabolism in the PVC showed no significant differences in demographics, neuropsychological characteristics, radiological findings, the prevalence of clinical features of DLB, or the severity and characteristics of parkinsonism. Only the onset age of probable RBD was significantly younger in patients with glucose hypometabolism in the PVC, whereas there were no differences in the onset ages of other examined clinical features. Moreover, the onset age of probable RBD was significantly correlated with the CMRglc in the PVC. These results suggest that metabolic reduction in the PVC may represent the effect of the pathophysiological process of DLB on RBD rather than a distinct condition in the disease progression of DLB. In brains of patients with DLB, the density of Lewy bodies is reportedly the lowest in the occipital cortex. Hypometabolism in the PVC is thought to reflect a disturbance of the neuronal projection from another part of the brain, although it is partly caused by primary degeneration of the occipital cortex.14 Satoh et al. reported that the regional CMRglc in the medial occipital cortex, but not in the lateral occipital cortex, changed significantly 3 months after cholinesterase inhibitors were started in patients with DLB.15 Mori et al. reported that regional cerebral blood flow in the occipital cortex was increased and visual hallucination was improved in response to cholinesteraseinhibiting medication in DLB patients.16 Shimada et al. demonstrated brain acetylcholinesterase (AChE) activity in patients with Lewy body disease, including
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Table 1. Comparisons of demographics, neuropsychological data and clinical features between patients with and without hypometabolism in PVC
Age at evaluation (years) Age at onset of dementia (years) Male (%) Duration of education (years) MMSE score WAIS-III Full scale IQ Verbal IQ Performance IQ WMS-R General memory Verbal memory Visual memory Attention/concentration Delayed recall Bender Gestalt test MRI Scheltens’ scale Left medial temporal lobe atrophy Right medial temporal lobe atrophy MRI Fazekas’ scale PVH DSWMH [123I]-MIBG scintigraphy Early H : M ratio (%) Delayed H : M ratio (%)
With glucose hypometabolism in PVC (n = 16)
Without glucose hypometabolism in PVC (n = 11)
74.6 ± 5.3 71.6 ± 5.5 75.0% 12.1 ± 2.3 22.0 ± 4.6 n = 11 94.7 ± 19.8 102.5 ± 18.7 86.5 ± 18.5 n = 11 86.5 ± 11.5 89.0 ± 9.3 86.6 ± 16.1 99.8 ± 11.1 85.2 ± 13.4 n = 14 99.4 ± 42.0 n = 16 1 [0, 1.75] 1 [0, 1] n = 16 1 [0.25, 1.75] 1 [0, 1.75] n = 12 1.84 ± 0.33 1.40 ± 0.22
76.5 ± 5.3 73.1 ± 5.2 72.7% 12.5 ± 2.8 22.8 ± 4.8 n = 10 99.1 ± 8.0 104.5 ± 9.2 92.1 ± 8.5 n = 10 85.4 ± 9.2 90.4 ± 7.6 80.9 ± 14.6 101.7 ± 11.1 80.0 ± 10.2 n = 11 76.0 ± 28.0 n = 11 1 [0, 2] 1 [0, 2] n = 11 1 [0, 1.0] 0 [0, 2.0] n=8 1.74 ± 0.29 1.31 ± 0.18
P-value P = 0.419 P = 0.491 P = 0.502 P = 0.751 P = 0.657 P = 0.522 P = 0.768 P = 0.397 P = 0.806 P = 0.712 P = 0.405 P = 0.702 P = 0.336 P = 0.127 P = 0.865 P = 0.577 P = 0.790 P = 0.942 P = 0.465 P = 0.317
Data are presented as the mean ± standard deviation, median [25%, 75%]. [123I]-MIBG scintigraphy, [123I]-metaiodobenzylguanidine scintigraphy; DSWMH, deep and sub-cortical white matter hyperintensity; H : M ratio, heart to mediastinum ratio; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PVC, primary visual cortex; PVH, periventricular hyperintensity; WAIS-III, Wechsler Adult Intelligence Scale-III; WMS-R, Wechsler Memory Scale-Revised.
DLB.17 They revealed that brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. Even de novo early PD patients exhibited significant reductions in AChE activity in the medial occipital cortex, suggesting that brain cholinergic dysfunction may precede the manifestation of motor dysfunction in PD. These reports suggest that glucose hypometabolism in the PVC may be related to cholinergic disturbance in patients with DLB. RBD, one of the suggestive clinical features of DLB, is a type of parasomnia that is characterized by a lack of motor inhibition during rapid eye movement (REM) sleep that leads to potentially harmful dream-
enacting behaviors.7 In a longitudinally followed cohort of 234 autopsy-confirmed dementia patients, a history of definite or probable RBD was present in 76% of 98 patients with autopsy-confirmed DLB.4 In contrast, only five of 136 patients without autopsy-confirmed DLB exhibited probable RBD. REM sleep without atonia was not confirmed using polysomnography in any of the five patients. These results suggest the close relation between RBD and DLB pathology. Moreover, Dugger et al. reported that 60% of autopsy-confirmed DLB patients developed probable RBD before or during the year of estimated dementia onset,3 suggesting that RBD may be related to the onset of DLB.
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Table 2. Comparison of clinical features between patients with and without hypometabolism in PVC
Clinical features Parkinsonism Prevalence (%) Age at onset UPDRS motor score Prevalence of tremor dominant type Visual hallucinations Prevalence (%) Age at onset Probable RBD Prevalence (%) Age at onset Duration (years) Olfactory disturbance Prevalence (%) Age at onset Constipation Prevalence (%) Age at onset Orthostatic dizziness Prevalence (%) Age at onset Urinary incontinence Prevalence (%) Age at onset Increased sweating Prevalence (%) Age at onset Increased salivation Prevalence (%) Age at onset Depression Prevalence (%) Age at onset Anxiety Prevalence (%) Age at onset Moodiness Prevalence (%) Age at onset Lack of motivation Prevalence (%) Age at onset
With glucose hypometabolism in PVC (n = 16)
Without glucose hypometabolism in PVC (n = 11)
P-value
68.8% 74.3 ± 4.6 19.8 ± 18.9 12.5%
81.8% 74.4 ± 4.3 16.4 ± 16.9 18.2%
P = 0.383 P = 0.932 P = 0.652 P = 0.545
75.0% 73.0 ± 5.8
72.7% 73.3 ± 5.8
P = 0.617 P = 0.926
75.0% 63.3 ± 10.6 10.1 ± 11.4
81.8% 72.1 ± 8.0 5.1 ± 5.4
P = 0.528 P = 0.049* P = 0.244
62.5% 61.2 ± 17.4
60% 63.5 ± 10.1
P = 0.609 P = 0.773
50.0% 62.8 ± 15.7
72.7% 65.6 ± 8.3
P = 0.218 P = 0.677
50% 64.1 ± 23.5
40% 70.5 ± 5.3
P = 0.464 P = 0.614
50% 72.8 ± 3.1
50% 76.6 ± 6.7
P = 0.656 P = 0.183
31.3% 70.0 ± 14.2
10% 75.0 ± 0
P = 0.225 P = 0.773
31.3% 70.8 ± 6.4
50% 71.8 ± 2.4
P = 0.293 P = 0.788
43.8% 66.3 ± 14.1
60% 71.2 ± 8.2
P = 0.344 P = 0.473
50% 70.6 ± 2.6
55.6% 71.0 ± 2.9
P = 0.560 P = 0.814
56.3% 70.9 ± 3.4
40% 76.3 ± 9.5
P = 0.344 P = 0.344
56.3% 74.1 ± 3.6
70% 59.8 ± 29.5
P = 0.391 P = 0.290
Data are presented as the mean ± SD. *Statistically significant P-values (P < 0.05). PVC, primary visual cortex; RBD, rapid eye movement sleep behavior disorder; UPDRS, Unified Parkinson’s Disease Rating Scale.
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Table 3. Demographic data, psychological data and clinical features of the DLB patients, and correlation of these to hypometabolism in the PVC Correlation to hypometabolism in the PVC Demographics Age at evaluation Age at onset of dementia Duration of education Psychological tests MMSE score WAIS-III (n = 21) Full scale IQ Verbal IQ Performance IQ WMS-R (n = 21) General memory score Verbal memory score Visual memory score Attention/concentration score Delayed recall score Bender Gestalt test score (n = 26) [123I]-MIBG scintigraphy (n = 20) Early H : M ratio Delayed H : M ratio Clinical features UPDRS score Age at onset of clinical features Parkinsonism Visual hallucination Probable RBD Olfactory disturbance Constipation Orthostatic dizziness Urinary incontinence Increased sweating Increased salivation Depression Anxiety Moodiness Lack of motivation
R = −0.074; P = 0.715 R = −0.064; P = 0.751 R = −0.098; P = 0.635 R = −0.160; P = 0.424 R = −0.010; P = 0.967 R = 0.027; P = 0.908 R = −0.030; P = 0.894 R = 0.090; P = 0.701 R = −0.070; P = 0.771 R = 0.210; P = 0.356 R = −0.060; P = 0.783 R = 0.250; P = 0.279 R = 0.310; P = 0.152 R = 0.125; P = 0.598 R = 0.184; P = 0.436 R = 0.140; P = 0.493 R = 0.052; P = 0.827 R = 0.049; P = 0.837 R = −0.430; P = 0.047* R = −0.133; P = 0.623 R = −0.088; P = 0.775 R = −0.254; P = 0.451 R = −0.289; P = 0.338 R = −0.205; P = 0.740 R = −0.124; P = 0.751 R = −0.099; P = 0.726 R = −0.168; P = 0.583 R = −0.312; P = 0.299 R = 0.372; P = 0.172
*Statistically significant P-values (P < 0.05). [123I]-MIBG scintigraphy, [123I]-metaiodobenzylguanidine scintigraphy; DLB, dementia with Lewy bodies; H: M ratio; heart, mediastinum ratio; MMSE, Mini-Mental State Examination; RBD, rapid eye movement sleep behavior disorder; UPDRS, Unified Parkinson’s Disease Rating Scale; PVC, primary visual cortex; WAIS-III, Wechsler Adult Intelligence Scale-III; WMS-R, Wechsler Memory Scale-Revised.
Although there is as yet little information regarding the existence of subtypes in patients with DLB,3 evidence that RBD may be an important marker of a particular subtype of PD is rapidly accumulating.18–22 Many recent studies suggest that symptoms of RBD can predict development of dementia, visual hallucinations, and cognitive fluctuation in patients with PD.22 Moreover, RBD has been associated with non-tremor-predominant form, symmetric disease, and increased autonomic dysfunction in patients with PD.8,19,21–23 These clinical characteristics are generally compatible with those in patients with DLB. Given that the reported occurrence of RBD in PD varies from 15 to 47%,24 RBD seems to be more common in patients with DLB. In the present study, the difference in the onset age of RBD between groups with and without glucose hypometabolism in the PVC raises the possibility of the existence of subtypes in patients with DLB. Because of the relatively small sample size in this study, it is possible that differences in other clinical variables exist between the two groups but do not reach statistical significance. Further studies with larger sample sizes and more detailed clinical evaluation will be needed to confirm our hypothesis. Kotagal et al. have recently investigated the correlation between RBD and a variety of neurotransmitter deficits based on neuroimages in patients with PD.25 They revealed that the presence of RBD symptoms in PD is associated with cholinergic denervation. Moreover, AChE inhibitor was reported to improve the symptoms of RBD,26 suggesting that cholinergic degeneration may play a role in the pathogenesis of RBD. Cholinergic denervation may be one of the common modes of pathogenesis, forming the link between RBD and metabolic reductions in the PVC. RBD clearly plays an important role in the pathogenesis of DLB. We recently reported on the variability in the patterns of cortical metabolism in patients with probable RBD: a subset of non-demented patients exhibited glucose hypometabolism in the PVC even when core features of DLB were absent.27 Many recent longitudinal studies have revealed that idiopathic RBD is a much more sensitive and specific prodromal marker of DLB than any other symptom, including olfactory and autonomic dysfunctions.4,7,19,21 If we are able to elucidate the link between the occurrence of RBD and the emergence of glucose hypometabolism in the PVC, the long prodromal phase of RBD could provide a critical opportunity for potential intervention with disease-modifying therapy for DLB.
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ACKNOWLEDGMENTS This study was supported in part by the Anti-Aging Research Center of Juntendo University School of Medicine, The Ogasawara Foundation for the Promotion of Science and Engineering, Nihon Medi-Physics, the 21st Novartis Foundation of Gerontological Research and the Japan Geriatrics Society (2011). The authors have no conflicts of interest.
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