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Geriatr Gerontol Int 2015

REVIEW ARTICLE

Prodromal dementia with Lewy bodies Hiroshige Fujishiro,1 Shinichiro Nakamura,2 Kiyoshi Sato3 and Eizo Iseki3 1

Department of Sleep Medicine, Nagoya University Graduate School of Medicine, Nagoya, 2Department of Neurology, Koshigaya Municipal Hospital, Koshigaya, and 3PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, Koto, Japan

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementing disorder after Alzheimer’s disease (AD), but there is limited information regarding the prodromal DLB state compared with that of AD. Parkinson’s disease (PD) and DLB share common prodromal symptoms with Lewy body disease (LBD), allowing us to use a common strategy for identifying the individuals with an underlying pathophysiology of LBD. Dysautonomia, olfactory dysfunction, rapid eye movement sleep behavior disorder (RBD) and psychiatric symptoms antedate the onset of dementia by years or even decades in patients with DLB. Although RBD is the most potentially accurate prodromal predictor of DLB, disease progression before the onset of dementia could differ between the prodromal DLB state with and without RBD. Experts who specialize in idiopathic RBD and DLB might need communication in order to clarify the clinical relevance of RBD with the disease progression of DLB. The presence of prodromal LBD symptoms or findings of occipital hypoperfusion/hypometabolism helps us to predict the possible pathophysiological process of LBD in non-demented patients. This approach might provide the opportunity for additional neuroimaging, including cardiac 123I-metaiodobenzylguanidine scintigraphy and dopamine transporter imaging. Although limited radiological findings in patients with prodromal DLB states have been reported, there is now a need for larger clinical multisite studies with pathological verification. The long prodromal phase of DLB provides a critical opportunity for potential intervention with disease-modifying therapy, but only if we are able to clearly identify the diversity in the clinical courses of DLB. In the present article, we reviewed the limited literature regarding the clinical profiles of prodromal DLB. Geriatr Gerontol Int 2015; ••: ••–••. Keywords: Alzheimer’s disease, Lewy body disease, mild cognitive impairment, neurocognitive disorder, Parkinson’s disease.

Introduction Many previous longitudinal studies have shown that specific patterns on neuropsychological testing and biomarkers, including neuroimaging and cerebrospinal fluid assays, in patients with amnestic mild cognitive impairment (MCI) predict progression to Alzheimer’s disease (AD).1 Based on the accumulating evidence of the pathophysiological process of AD, the National Institute on Aging and the Alzheimer’s Association has recently revised the diagnostic criteria for AD.1,2 This set of criteria assumes that it is possible to identify the likely primary cause of the clinical symptoms in individuals with AD pathophysiological processes. According to the degree of cognitive dysfunction, symptomatic individu-

Accepted for publication 19 December 2014. Correspondence: Dr Hiroshige Fujishiro MD PhD, Department of Sleep Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan. Email: [email protected]

© 2015 Japan Geriatrics Society

als with AD pathophysiological processes are classified as MCI due to AD and AD dementia. This approach could allow for an earlier therapeutic intervention capable of preventing or at least delaying the clinical appearance of AD. Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementing disorder after AD in some series.3 DLB is clinically characterized by progressive dementia that is frequently accompanied by parkinsonism and visual hallucinations. Neurodegenerative disorders leading to dementia are chronic diseases with a long predementia phase, but there is limited information regarding the prodromal DLB state compared with that of AD.4–8 Based on the clinical criteria of the Third Consortium on DLB (CDLB), the clinical diagnosis of DLB requires the presence of dementia, which is defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Because of this requirement, the non-demented patients with specific clinical features of DLB do not meet the clinical criteria for an early diagnosis. Thus, it is of concern that the doi: 10.1111/ggi.12466

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prodromal DLB patients whose cognitive deficits do not interfere with their capacity for independence in everyday activities are being diagnosed based on the CDLB diagnostic criteria. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) has recently been released.9 Neurocognitive disorders in the DSM-V are defined so as to cover, in a more appropriate way, all the entities that potentially lead to dementia. In the manual, symptomatic individuals with AD pathophysiological processes are classified as suffering from a mild or major neurocognitive disorder as a result of AD according to the degree of cognitive dysfunction. In the same way, symptomatic individuals with DLB pathophysiological processes are classified as suffering from a mild or major neurocognitive disorder with Lewy bodies (NCDLB). Major NCDLB nearly corresponds to DLB, whereas mild NCDLB is included in the prodromal DLB state. Because sharp demarcations between individuals with some cognitive deficits and dementia patients are difficult to identify, this revision in the DSM-V is useful in that it allows clinicians to incorporate this continuum of impairment into clinical practice. The clinical implications of these changes are noteworthy in that specification of the diagnoses in the DSM-V would allow clinicians to internationally utilize these diagnoses more systematically for the early detection of patients with DLB pathophysiological processes. Increasingly, clinical research has focused on using the prodromal phase of DLB to identify the non-demented individuals with DLB pathophysiological processes, because several treatments with disease-modifying or neuroprotective potential in DLB are under investigation. There is, however, little literature that focuses on the clinical characteristics of prodromal DLB. This could be because the clinical conditions corresponding to prodromal DLB have not been defined. In the present review, the term prodromal DLB is used to represent clinical conditions with underlying DLB pathophysiological processes in the predementia phase. In order to clarify the diversity in the clinical courses of DLB, early manifestations other than cognitive dysfunction before the onset of dementia were included as prodromal DLB symptoms. We first mention a conceptual framework to understand the prodromal DLB state based on recent clinicopathological studies. We then summarize the limited literature regarding clinical, neuropsychological and radiological findings of prodromal DLB.

Parkinson’s disease and DLB share prodromal symptoms with Lewy body disease Lewy body disease (LBD), including Parkinson’s disease (PD) and DLB, is defined pathologically as degeneration in the central, peripheral and autonomic nervous 2

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system associated with Lewy bodies (LB).10 The common pathological basis supports the idea that the clinical features overlap between them. PD is clinically characterized by a motor syndrome featuring rigidity, bradykinesia and rest tremors, which are related to striatonigral dopaminergic denervation associated with LB. Non-motor symptoms, including autonomic dysfunction, olfactory dysfunction and rapid eye movement (REM) sleep behavior disorder (RBD), and depression are increasingly recognized as clinical signs that enable the early detection of PD, because some of these symptoms antedate motor dysfunctions by years or even decades.11,12 Recent clinicopathological studies have reported that olfactory dysfunction, depression, RBD and reduced bowel movement frequency late in life are associated with incidental LB; that is, the presence of LB in the brains of deceased individuals with no history of parkinsonism or dementia while alive.13–17 Incidental LB occur in 8–17% of neurologically normal people over the age of 60 years.18–20 Braak et al. developed a neuropathological staging scheme for PD and proposed that PD primarily starts in the caudal brainstem, with rostral spread of LB pathology over time.21 Although incidental LB are often assumed to represent preclinical PD, some cases with incidental LB have diffuse cortical pathology inconsistent with preclinical PD.20,22 These cases failed to fit the PD staging scheme, based on the fact that some anatomical regions in the brainstem and basal forebrain were unaffected. This suggests that incidental LB could represent the prodromal state of DLB as well as that of PD. The Third CDLB reported that DLB is defined as a clinicopathological entity with a specific constellation of clinical features, and the proposed pathological scheme of likelihood that observed LB pathology explains the clinical syndrome.3,23,24 Various non-motor symptoms of PD were included in the Third CDLB clinical criteria as suggestive and supportive clinical features of DLB. Although the pattern in the development of DLB pathology remains unclear, incidental LB have already appeared before the progression of LB pathology reaches a certain threshold of dementia. Given the common pathological basis between PD and DLB, this concept might allow us to identify non-demented individuals with DLB pathophysiological processes based on the application of methods used to identify prodromal PD. We have recently reported the clinical courses regarding non-motor symptoms of PD in 90 patients with probable DLB based on a retrospective survey.25 In this series, the mean age of memory loss onset was 74.9 ± 9.7 years. The average duration of non-motor symptoms of PD that preceded or followed the onset of memory loss was calculated. Non-motor symptoms of PD, including constipation, olfactory dysfunction, depression, RBD and dysautonomia, were present in 79 © 2015 Japan Geriatrics Society

Prodromal DLB

of 90 patients (87.8%) with probable DLB before or at the time of memory loss onset. These symptoms preceded the onset of memory loss by 1.2–9.3 years. These results suggest both a diversity in clinical courses and the long-term nature of the disease, supporting the idea that PD and DLB share common prodromal symptoms with LBD.

Clinicopathological differences between PD dementia and DLB LB dementia encompasses two clinicopathological syndromes associated with LB: PD dementia (PDD) and DLB. The only basis for a clinical distinction between these diseases is whether parkinsonism or dementia developed first. The onset of dementia occurs after 12 months of parkinsonism in PDD, whereas dementia either precedes parkinsonism or both symptoms occur concurrently in DLB within 12 months.3 Recent clinicopathological and neuroimaging studies reported that cerebral amyloid burden contributes to the timing of the onset of dementia relative to that of parkinsonism in PDD and DLB. Many studies showed that DLB patients exhibited significantly more abundant amyloid burden than did PDD patients, although both clinical phenotypes had abundant cortical LB.10,26–30 These results are broadly consistent with cerebrospinal fluid studies regarding LBD.31–33 Although it remains unclear why the degree of cerebral amyloid burden might relate to the determination of clinical phenotypes in LB dementia, a potential explanation has been proposed. A recent clinicopathological study has shown that neuronal density in the substantia nigra was linearly linked with the score on the motor section of the Unified Parkinson Disease Rating Scale (UPDRS) in LBD, which includes both PDD and DLB.34 It is likely that PDD patients begin to show dementia only after reaching a critical level of nigra degeneration. In contrast, DLB patients might begin to show dementia before reaching that critical level of nigra degeneration, which is the typical symptom threshold. Many recent studies have reported that amyloid deposition enhances the development of cortical α-synuclein lesions.35–39 Given that the presence of cortical LB is related to cognitive impairment in LB dementia, cortical amyloid deposition could prompt the onset of dementia before a critical level of neuronal loss has occurred in the substantia nigra.40,41 This hypothesis enables us to understand the clinical and pathological continuum between PDD and DLB. Furthermore, this concept might prompt us to use a common strategy for identifying the non-demented individuals with the underlying pathophysiology of LBD as being in the predementia state of PDD/DLB. © 2015 Japan Geriatrics Society

Clinical profiles of prodromal DLB RBD RBD, one of the suggestive clinical features of DLB, is a type of parasomnia that is characterized by a lack of motor inhibition during REM sleep and that leads to potentially harmful dream-enacting behaviors.42 The clinical diagnosis of definite RBD requires the presence of REM sleep without atonia using polysomnography. Increasing evidence suggests that RBD is a heralding feature associated with evolving α-synucleinopathyrelated neurodegenerative disorders, including PD and DLB. Boeve et al. reported clinicopathological correlations in a large number of cases with RBD.43 Of 170 patients with probable RBD, 158 patients (93%) had synucleinopathy at autopsy. Of 80 patients with PSG confirmed RBD, 78 patients (98%) had synucleinopathy at autopsy. In a longitudinally followed cohort of 234 autopsy-confirmed dementia patients, a history of definite or probable RBD was present in 74 (76%) of the 98 patients with autopsy-confirmed DLB.44 In contrast, just five (3%) of the 136 patients without autopsyconfirmed DLB showed probable RBD. REM sleep without atonia was not confirmed using polysomnography in any of the five patients. These results support a reasonably specific association of RBD with DLB pathology in the case of patients with dementia. Furthermore, the same cohort study reported that 60% of autopsy-confirmed DLB patients developed RBD before or during the year of estimated dementia onset, suggesting that RBD plays an important role in the pathogenesis of DLB.45 The recent longitudinal studies focusing on the risk of neurodegenerative disease in patients with idiopathic RBD provided a high predictive value for the development of PD/DLB. The prevalence of evolving neurodegenerative disorders in previous studies is summarized in Table 1.46–55 These follow-up studies showed that patients with idiopathic RBD have up to an 80% risk of developing a defined neurodegenerative synucleiopathy. The profoundly high risk of neurodegenerative disease associated with idiopathic RBD is the most potentially accurate prodromal predictor of PD/DLB. Thus, as studies of idiopathic RBD allow for prospective testing of predictive markers of developing dementia, several clinical cohort studies of idiopathic RBD mainly in sleep centers are underway. A subset of patients with DLB, however, shows no RBD before the development of dementia. Given that clinical characteristics differ between PD with and without RBD, disease progression before the onset of dementia might differ for the prodromal DLB state with and without RBD.56–59 It is unlikely that only follow-up studies of patients with idiopathic RBD can clarify the full disease progression of DLB. Because there is limited information regarding the existence of clinical subtypes |

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Table 1 Follow-up studies of idiopathic rapid eye movement sleep behavior disorder Study

n

Age at baseline (years)

Follow-up period

Parkinson’s disease

MCI

Dementia

MSA

Schenck et al.46 (1996) Iranzo et al.47 (2006)

28 44

63.1 74.1 (± 6.5)

5.1 years 5.1 years

11 9 (including 2 PDD)

NA 4

0 1

Postuma et al.48 (2009) Iranzo et al.49 (2010) Fantini et al.50 (2011) Iranzo et al.51 (2011) Postuma et al.52 (2011)

93 43 24 20 62

65.4 70.1 69.5 70.5 67.8

5.2 years 2.5 years 26.3 months 3 years 5 years

14 5 3 3 7 (including 3 PDD)

NA NA NA NA NA

Boot et al.53 (2012) Wing et al.54 (2012) Schenck et al.55 (2013) Iranzo et al.56 (2013)

44 91 26 44

78 (75, 82) 65.5 (± 9.9) NA 74.1 (± 6.5)

15 months 5.6 years 21 years 12 years

1 8 13 16 (including 5 PDD)

14 25 NA 5

1 6 (excluding 2 PDD) 11 2 0 0 14 (excluding 3 PDD) 0 11 6 14 (excluding 5 PDD)

(± 9.3) (± 6.8) (± 7.3) (± 6.0) (± 9.9)

1 1 0 0 0 0 0 2 1

Follow-up numbers, age at baseline (mean ± SD or median, 25th–75th percentile) and follow-up period are summarized. The numbers of evolving neurodegenerative disorders during the observation period were also listed. MCI, mild cognitive impairment; MSA, multiple system atrophy; NA, not available; PDD, Parkinson’s disease dementia.

in patients with DLB, it will be necessary to clarify the clinical relevance of RBD with disease progression in DLB.

Olfactory dysfunction A retrospective survey showed that anosmia/hyposmia before or at the onset of memory loss was present in 34 (37.8%) of 90 patients with probable DLB.25 In this series, the mean duration of olfactory dysfunction preceding the onset of memory loss was 12.4 years. When the prevalence of olfactory dysfunction at the onset of memory loss based on a simple standardized worksheet was investigated, DLB patients showed a significantly higher prevalence of anosmia/hyposmia (41.1%) than did AD patients (6.2%) and normal controls (6.7%).8 The relatively high prevalence of anosmia/hyposmia can be regarded as a common feature in the disease process of DLB, although olfactory dysfunction is not included in the Third CDLB criteria for DLB.3 Williams et al. reported that the olfactory impairment is more marked in patients with mild DLB than those with mild AD.60 These results suggest that carefully noting olfactory dysfunction could aid DLB diagnosis in the early stage. In patients with idiopathic RBD, previous studies have shown that olfactory dysfunction is also frequently observed.61,62 Based on a clinical cohort study of idiopathic RBD, Postuma et al. reported that olfactory dysfunction was measurable at least 5 years before the onset of LBD in patients with idiopathic RBD.62 4

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Autonomic dysfunction Yamanaka et al. reported a 65-year-old man with probable DLB whose isolated autonomic failure preceded the onset of dementia by over 10 years.63 His severe autonomic failure included urinary frequency, orthostatic hypotension and erectile dysfunction. Kaufmann et al. also reported an autopsy-confirmed DLB case who showed preceding isolated autonomic failure.64 This Caucasian male patient developed frequent syncopal episodes at the age of 73 years. His autonomic dysfunction, including erectile dysfunction, urinary urgency and severe constipation, preceded the onset of parkinsonism and dementia by several years. These prodromal clinical conditions were consistent with pure autonomic failure. The presence of these cases suggests that DLB might present autonomic failure as an initial symptom. Kosaka reported the clinical characteristics of 37 Japanese patients with diffuse LBD at autopsy.65 The initial symptom was Shy-Drager syndrome in three patients. Postuma et al. reported the characteristics of autonomic dysfunction, including systolic blood pressure drop, urinary dysfunction, constipation and erectile dysfunction, in patients with idiopathic RBD who were followed annually in a prospective clinical cohort.66 Of 91 patients with idiopathic RBD, 17 developed PD and 15 developed DLB during the observation period. The estimated prodromal interval was approximately 10–20 years based on regression analysis. It is of note that there were no significant differences in estimated prodromal intervals between patients with RBD who developed PD and those who developed DLB. © 2015 Japan Geriatrics Society

Prodromal DLB

Abnormalities of autonomic function are significantly worse in patients with PD/DLB compared with agematched controls even in prodromal periods. The authors mentioned that the predictive value of abnormalities of autonomic function for patients with idiopathic RBD might be limited by the long prodromal interval.

Psychiatric symptoms Molano et al. reported an autopsy-confirmed DLB patient who developed recurrent fully formed visual hallucinations 3 years before the onset of cognitive impairment.4 This patient was initially thought to have Charles Bonnet syndrome because of the absence of any other neurological signs or symptoms. Iida et al. reported a 60-year-old Japanese man who developed delusions of pursuit, and control and auditory hallucinations with no prominent affective symptoms.67 At the age of 55 years, he became alternatively depressive and hypomanic. His clinical diagnosis was schizoaffective disorder. At the age of 59 years, he developed dementia with visual hallucinations and extrapyramidal symptoms. Neuroimaging studies showed occipital hypoperfusion in brain single-photon emission computed tomography (SPECT) and reduced cardiac 123Imetaiodobenzylguanidine (MIBG) uptake, which were consistent with the characteristics of DLB. The authors noted that his clinical psychiatric symptoms before the age of 59 years might have been prodroms of DLB because of his late onset age for schizoaffective disorder. According to the retrospective survey, visual hallucination preceded the onset of memory loss in six (6.7%) of 90 patients with probable DLB.25 In Kosaka’s report, seven of 37 Japanese patients with diffuse LBD at autopsy showed psychotic features as initial symptoms.65 One patient showed mild dementia without parkinsonism during the clinical course and was diagnosed with senile psychosis. These reports suggest that delusions and hallucinations can occur before the onset of cognitive changes. Depression is common in patients with DLB, and occurs at a higher prevalence than in patients with AD.68 A retrospective survey reported that 17 of 90 patients with probable DLB (18.9%) had a history of visiting a physician for depression and taking antidepressant agents at or before the onset of memory loss.25 In the study, the mean of prodromal duration of depression relative to the onset of memory loss was 7.2 ± 12.0 years. Poewe and Wenning reported that 21 of 239 autopsy-confirmed cases with Lewy bodies had an initial clinical diagnosis of depression.69 Takahashi et al. reported that 23 of 167 patients (13.8%) with mood disorder as the initial diagnosis at admission were re-diagnosed with DLB through examinations.70 Of the 23 DLB patients, 22 were diagnosed with major © 2015 Japan Geriatrics Society

depressive disorder and one with bipolar I disorder based on the fourth edition, text revision, of the DSM at admission. These results suggest that depression might be common as an initial symptom in the disease process of DLB. Depression and DLB share an overlap of symptoms, such as reduced facial expression, sleep problems and psychomotor retardation, which could contribute to patients with DLB receiving an initial clinical diagnosis of depression. It is crucial to clinically diagnose DLB in elderly depressed patients accurately because of the differences in prognosis and management. Onofrj reported the high prevalence of somatoform disorder based on fourth edition, text revision, of the DSM in patients with DLB in a clinical cohort of 942 patients with neurodegenerative disorders.71 The frequency of somatoform disorder was higher in 15 of 124 patients with DLB (12%) and 29 of 412 patients with PD (7%) than in those with other neurodegenerative diseases (0–3%). In this series, symptoms of somatoform disorder preceded the clinical diagnosis of DLB by 6 months to 10 years in all patients with DLB. Semistructured interviews with patients and caregivers reported several aspects of histrionic health concerns and medically unexplained symptoms, as confirmed by a general practitioner before the clinical diagnosis of DLB, in 28 of 124 (23%) patients with DLB.

Mild parkinsonian signs Parkinsonism is a gradually progressive disorder, which is related to striatonigral dopaminergic denervation associated with LB in PD/DLB. Although the occurrence of at least two of the cardinal motor signs, including bradykinesia, and either rigidity, tremor or postual instability, are required for a clinical diagnosis of PD, with motor criteria as one of the core features of DLB being unclear. Mild parkinsonian signs have been described during the clinical examination of elderly individuals without known neurological disease, including PD/DLB.72 Because MPS can commonly occur at the prodromal DLB stage, it would be useful to identify those individuals with MPS who are at high risk for the development of DLB. When assessed by a structured neurological examination, parkinsonian signs occur in approximately 30–40% of communitydwelling elderly people.73–75 Furthermore, the prevalence of these motor signs increases with age. The previous study reported that the assessment of mild motor signs in the elderly population using the UPDRS does not reliably increase the identification of at-risk individuals for PD.76 Given that the onset age is usually higher in DLB patients than in those with PD, it would be more difficult to identify at-risk individuals for DLB in an elderly population based on mild parkinsonian signs. |

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Postuma et al. have recently reported prodromal parkinsonism motor changes before the onset of DLB in a cohort study of patients with idiopathic RBD.77 During follow up, 20 patients developed parkinsonism according to the UK Brain Bank criteria.78 Of the 20 patients, nine had also developed dementia within 1 year of parkinsonism diagnosis and were clinically diagnosed as DLB; the remaining 11 were clinically diagnosed as PD because of no dementia within 1 year of parkinsonism diagnosis. A UPDRS score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before the clinical diagnosis of PD/DLB. On regression analysis, the estimated prodromal interval for UPDRS in DLB was 6.0 years. UPDRS progressed 2.1 points per year in prodromal DLB.

Neuropsychological profiles of prodromal DLB To date, there have been only a few studies focusing on neuropsychological profiles of prodromal DLB. Ferman et al. recently reported the characteristics of neuropsychological profiles of MCI patients who progressed to probable DLB in a longitudinal clinical cohort.79 In that study, patients with non-amnestic MCI were more likely to develop DLB. In contrast, those with amnestic MCI were more likely to develop probable AD. Of 49 MCI patients who progressed to clinically probable DLB, 43 (88%) presented initially with attention and/or visuospatial impairment, and 16 (32%) presented with memory impairment. A longitudinal clinicopathological study in the same group reported the detailed clinical profiles of eight MCI patients who were prospectively followed and were subsequently found to have autopsyconfirmed LBD.4 All patients showed attention and/or visuospatial impairment at MCI stages. Three patients (37.5%) showed memory impairment at MCI stages; this prevalence is similar to that in the previous clinical cohort. Although these findings suggest that multiple patterns of cognitive impairment are present in prodromal DLB patients, they usually have the non-amnestic MCI subtype rather than the amnestic MCI subtype. Retrospective clinicopathological studies reported visuospatial deficits at the early stage of DLB predict the occurrence of visual hallucination and rapid cognitive decline.80–82 Visuospatial dysfunction in the early stage is a key clinical feature for the differential diagnosis of DLB from other neurodegenerative dementias, even before visual hallucinations appear. Attention impairment can occur in many medical conditions, including depression and sleep disorders. Visuospatial dysfunction might be useful in identifying individuals at the prodromal DLB stage and in predicting their clinical courses. 6

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Radiological profiles of prodromal DLB Cardiac MIBG scintigraphy The time-course of cardiac sympathetic degeneration is poorly understood in DLB, although many comparative diagnostic studies of AD and DLB have been carried out using MIBG scintigraphy.83,84 In particular, it remains unclear whether reduced cardiac MIBG uptake is observed in the prodromal DLB state.25 Recent studies showed that patients with idiopathic RBD, which represents a prodromal phase of PD/DLB, exhibited reduced cardiac MIBG uptake.85,86 Given that RBD precedes the onset of dementia in over 50% of DLB patients, it is likely that many prodromal DLB patients with RBD show reduced cardiac MIBG uptake.45 In contrast, it remains unknown whether reduced cardiac MIBG uptake is observed in prodromal DLB patients without RBD. Sakakibara et al. reported amnestic MCI patients with low uptake in cardiac MIBG scintigraphy.87 A total of 13 (30%) of 44 amnestic MCI patients in their memory clinic showed low MIBG uptake. In this series, the mean age and the mean Mini-Mental State Examination score were 78.9 years (range 70–84 years) and 24.8 points (range 21–30 points), respectively. In seven of 13 MCI patients, visual hallucinations and/or RBD were present. Furthermore, various types of dysautonomia, including nocturia, urinary incontinence, constipation and postural hypotension, were observed in the majority of these MCI patients. Although it remains unknown whether these MCI patients represent the prodromal DLB state, clinical characteristics of these MCI cases correspond to those of DLB. The presence of these cases suggests that reduced cardiac MIBG uptake can be observed at the MCI stage, even when patients show a lack of RBD. We recently reported nondemented patients with probable RBD who were followed until conversion to probable DLB in a memory clinic. Although these cases showed reduced cardiac MIBG uptake, it remains unknown whether nondemented patients without RBD showed reduced cardiac MIBG uptake before the conversion to probable DLB.25,88,89 Because previous neuropathological studies showed that cardiac sympathetic denervation occurs in the early disease process of LBD, cardiac MIBG scintigraphy might prove to be a useful radiological method for identifying the prodromal DLB state.90,91 Further longitudinal follow-up studies will be required to clarify the time-course of cardiac MIBG reuptake in nondemented patients who develop DLB.

Striatal dopamine transporter Severe dopaminergic nigrostriatal degeneration occurs in DLB, but not in AD, offering a biological diagnostic marker.92 Low dopamine transporter (DAT) uptake in basal ganglia shown by SPECT or positron emission © 2015 Japan Geriatrics Society

Prodromal DLB

tomography (PET) imaging is included as one of the suggestive features in the criteria for the clinical diagnosis of DLB.3 A high correlation between abnormal DAT binding and a clinical diagnosis of probable DLB has been shown in a pivotal multicenter study. Abnormal DAT scans had a mean sensitivity of 78% for distinguishing clinically probable DLB from AD, with a specificity of 90% for excluding non-DLB.93 However, it remains unclear whether decreased striatal DAT binding is observed in prodromal DLB patients. It has been estimated that clinical symptoms of parkinsonism develop after at least 50% cell death of dopaminergic neurons in the substantia nigra.94,95 This suggests that there is a period during which the disease has started, but definitive symptoms or motor signs sufficient to permit a diagnosis have not yet appeared. Siepel et al. reported a follow-up study of patients without full clinical DLB syndrome showing abnormal DAT binding.96 All seven patients developed a moderate-to-severe parkinsonism and marked cognitive fluctuations during the follow-up period (median observation time: 3.4 years, range 2–5 years), although three had no parkinsonism at baseline. Two patients, who showed no core features or RBD at baseline, were converted to probable DLB during the follow-up period. The authors noted that DAT scans detect nigrostriatal degeneration before the full clinical DLB syndrome has developed.

Occipital hypoperfusion/hypometabolism on SPECT/PET scan Significant occipital hypoperfusion/hypometabolism, particularly in the primary visual cortex, is considered to support a diagnosis of DLB, and is used to distinguish DLB from AD with high sensitivity and specificity.84,97 Thus, occipital hypoperfusion/hypometabolism shown by SPECT or PET imaging is included as one of the supportive features in the criteria for the clinical diagnosis of DLB.3 Because a subset of patients with DLB shows the occipital findings in clinical practice, it will be necessary to clarify the time-course of the occipital hypoperfusion/hypometabolism in DLB. Whether occipital hypoperfusion/hypometabolism is observed in the prodromal DLB state is of critical importance. Sakakibara et al. reported 13 patients with amnestic MCI who showed low uptake in cardiac MIBG scintigraphy. In this series, five of 12 patients (42%) who underwent SPECT also showed occipital hypoperfusion.87 We recently reported non-demented patients with metabolic reduction in the primary visual cortex on [18F]-fluoroD-glucose PET scans.88,98 It is noteworthy that patients with the metabolic pattern who show no dementia nevertheless show certain other clinical features of DLB, mainly probable RBD, which can be considered one of the prodromal states of DLB. Furthermore, continued follow-up study (mean follow-up period: 44 ± 5 months) © 2015 Japan Geriatrics Society

showed that a subset of non-demented patients with glucose hypometabolism in the primary visual cortex exhibited progression to probable DLB.99 In this series, the spatial profiles of reduced glucose metabolism at baseline could help to define the distinct prognostic subgroup that has a greater risk of conversion to DLB. Converters had lower glucose hypometabolism in the parietal and the lateral occipital cortex compared to non-converters. Further multicenter studies with larger populations and longer observation periods until autopsy are required to confirm these findings. Multimodality imaging studies by Kantarci et al. reported that the specific regional hypometabolic pattern in the occipital and posterior parietotemporal lobe is independent of the amyloid pathology in DLB.100 Recent multiple imaging modalities that are sensitive to different components of the disease process can be used to clarify the neurobiological basis of the distinct prognostic subgroup that has a greater risk of conversion to DLB.

Conclusions PD and DLB share common prodromal symptoms with LBD, allowing us to use a common strategy for identifying the individuals with an underlying pathophysiology of LBD. Dysautonomia, olfactory disfunction, RBD and psychiatric symptoms antedate the onset of dementia by years or even decades in patients with DLB. Furthermore, these LBD symptoms occur before or after the onset of dementia, suggesting the diversity in the clinical courses of DLB. The profoundly high risk of neurodegenerative disease associated with idiopathic RBD is the most potentially accurate prodromal predictor of PD/DLB. Thus, several clinical cohort studies of idiopathic RBD mainly in sleep centers are underway. A subset of patients with DLB, however, shows no RBD before the development of dementia. Given that clinical characteristics differ between PD with and without RBD, disease progression before the onset of dementia might differ for the prodromal DLB state with and without RBD. It is unlikely that only follow-up studies of patients with idiopathic RBD can clarify the full disease progression of DLB. It might require the communication between experts who specialize in idiopathic RBD and DLB to elucidate clinical relevance of RBD with the disease progression in DLB. The presence of the clinical history of prodromal DLB symptoms helps us to predict the possible pathophysiological process of LBD in non-demented patients. Findings of occipital hypoperfusion/hypometabolism also suggest underlying LBD. This approach might provide the opportunity for additional neuroimaging, including cardiac MIBG scintigraphy and dopamine transporter imaging. Although limited radiological findings in patients with prodromal DLB states have been reported, there is now a need for larger clinical multisite studies |

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with pathological verification. The long prodromal phase of DLB provides a critical opportunity for potential intervention with disease-modifying therapy, but only if we are able to clarify the diversity in the clinical courses of DLB.

Acknowledgments This study was supported in part by the 21st Novartis Foundation of Gerontrological Research and the Japan Geriatrics Society (2011), and a Grant-in-Aid for Young Scientists (B) 20536924 from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Disclosure statement The authors declare no conflict of interest.

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