Yuhei Chiba

Retrospective Survey of Prodromal Symptoms in Dementia with Lewy Bodies: Comparison with Alzheimer's Disease

Background: Non-motor symptoms are recognized to enable the early detection of Parkinson’s disease (PD). It remains unknown when those symptoms appear in dementia with Lewy bodies (DLB). Method: We investigated the prevalence of 15 non-motor symptoms of PD at the onset of memory loss based on a standardized worksheet in 34 patients with DLB, 32 patients with Alzheimer’s disease (AD) and 30 normal controls. Results: DLB patients exhibited a significantly higher prevalence of olfactory dysfunction, constipation, increased saliva and signs of rapid eye movement sleep behavior disorder at the onset of memory loss than AD patients and normal controls. Conclusions: Paying attention to non-motor symptoms of PD may help DLB diagnosis in the early stage, especially in terms of its differentiation from AD.

Dementia with Lewy bodies: early diagnostic challenges.

Dementia with Lewy bodies (DLB) is defined pathologically as neurodegeneration associated with Lewy bodies (LB). LB‐related symptoms, including olfactory dysfunction, dysautonomia, and mood and sleep disorders, are increasingly recognized as clinical signs that enable the early detection of DLB, because these symptoms often antedate dementia by years or even decades. It remains unknown if the clinical history of LB‐related symptoms is sufficient for the prodromal state of DLB to be suspected in memory clinics. We retrospectively investigated the clinical courses, including olfactory dysfunction, dysautonomia, depression, and rapid eye movement sleep behaviour disorder, of 90 patients with probable DLB. The timing of LB‐related symptoms that preceded or followed relative to the onset of memory loss was calculated. LB‐related symptoms were present in 79 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 between 1.2 and 9.3 years. We also report on four non‐demented patients with a clinical history of LB‐related symptoms in our memory clinic. All four patients showed reduced cardiac [123I]‐metaiodobenzylguanidine levels. Moreover, [18F]fluoro‐D‐glucose positron emission tomography scans revealed glucose hypometabolism in the occipital cortex in two patients. One patient converted to probable DLB with the development of parkinsonism 2 years after major depression was diagnosed. Based on a clinical history of LB‐related symptoms, we propose a conceptual framework to identify these symptomatic but non‐demented individuals that led us to suspect the underlying pathophysiology of Lewy body disease. Further prospective study is warranted to determine the clinical significance of LB‐related symptoms in non‐demented patients.

A follow up study of non-demented patients with primary visual cortical hypometabolism: Prodromal dementia with Lewy bodies

We previously reported non-demented patients with glucose hypometabolism in the primary visual cortex (PVC), which is the preferentially affected region in patients with dementia with Lewy bodies (DLB). It remains unknown, however, whether these patients represent a prodromal DLB state. Eleven non-demented patients who attended our memory clinic for more than three years (mean follow-up period: 44 ± 5 months) were examined. All the patients had glucose hypometabolism in the PVC on [(18)F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scans at baseline. Four patients, including one with a clinical history of occipital bleeding, exhibited no core or suggestive features of DLB. Seven patients reported recurrent nocturnal dream-enactment behavior, which is consistent with probable rapid eye movement (REM) sleep behavior disorder (RBD). The condition of the patient with occipital bleeding was stable, which is consistent with an underlying non-neurodegenerative disorder. Of the remaining 10 patients, 5 had stable cognitive conditions (non-converters) and 5 exhibited progression to dementia (converters). The clinical diagnoses of 4 patients with probable RBD were changed to probable DLB. Despite no differences in psychological profiles at baseline between non-converters and converters, the initial pattern of cortical metabolism differed: converters had lower glucose hypometabolism in the parietal and the lateral occipital cortex compared to non-converters. The metabolic reduction in the PVC is present in patients with prodromal DLB. Moreover, 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.

Anti-glutamate receptor ɛ2 antibodies in psychiatric patients with anti-thyroid autoantibodies--a prevalence study in Japan.

Patients with anti-thyroid antibodies (ATAs) present various kinds of psychiatric conditions. When these psychiatric patients with ATAs (PPATs) show responsiveness to immunotherapy, they are frequently diagnosed with a diffuse progressive type of Hashimotos encephalopathy (HE). Anti-glutamate receptor ɛ2 subunit (GluRɛ2) antibodies have previously been reported in HE patients. However, it is unclear whether there is any relationship between PPATs, including HE patients, and anti-GluRɛ2 antibodies. We investigated anti-GluRɛ2 antibodies in the serum and cerebrospinal fluid (CSF) of 15 PPATs, and we compared the results with those of 11 patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an anti-glutamate receptor antibody-related disease. We then compared the neuropsychiatric symptoms between the PPATs with and without anti-GluRɛ2 antibodies. The prevalence of anti-GluRɛ2 antibodies was significantly higher in the CSF than in the serum of PPATs (41.7% versus 6.7%; p=0.040). The prevalence of anti-GluRɛ2 antibodies was slightly higher in the CSF of PPATs than NPSLE patients. PPAT-GluR(+)s showed a significantly higher prevalence of emotional instability (100% versus 33.3%; p=0.03) and also showed a significantly lower prevalence of delusions (0% versus 100%; p=0.001) and hallucinations (17% versus 83%; p=0.038) than PPAT-GluR(-)s. Our results suggest that anti-GluRɛ2 antibodies may be associated with the neuropsychiatric manifestation of PPATs.

Clinical profiles of dementia with Lewy bodies with and without Alzheimer's disease-like hypometabolism

It is well known that Alzheimers disease (AD)‐type pathology is commonly present in dementia with Lewy bodies (DLB) brains and that the degree of AD‐type pathology has an influence on the clinical characteristics of DLB. Although significant hypometabolism in the temporoparietal/precuneus on [18F]fluoro‐d‐glucose (18F‐FDG) positron emission tomography (PET) scans is considered to support a diagnosis of AD, some DLB patients also exhibit this metabolic pattern. The clinical significance of the metabolic pattern on DLB remains unknown.

Impaired heart rate variability in patients with dementia with Lewy bodies: Efficacy of electrocardiogram as a supporting diagnostic marker.

OBJECTIVE It has been suggested that impaired heart rate variability (HRV) may be an early sign of Parkinsons disease (PD). The aim of this study was to determine whether HRV can be employed in order to differentiate between dementia with Lewy bodies (DLB) and Alzheimers disease (AD). METHODS We examined HRV in 30 probable DLB patients (16 men and 14 women; mean age, 79.9 years; SD, 4.7 years), and 30 probable AD patients (15 men and 15 women; mean age, 79.8 years; SD, 5.6 years), compared with that in 20 age- and sex-matched controls. Subjects with other causes of impaired HRV were excluded. HRV was determined using the RR intervals of a 5-min electrocardiogram recording. Measurements of beat-to-beat RR variability, including time domains [(RR-standard deviation (SDNN), percentage of consecutive RR intervals differing by more than 50 msec (pNN50), and root mean square difference of successive RR intervals (RMSSD)), and frequency domains [very low- (VLF), low- (LF), and high-frequency (HF) components, and total spectral power (Total power)], were assessed retrospectively. The association between these HRV parameters and cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphy were investigated in 22 probable DLB patients. RESULTS DLB group showed significant decreases compared to AD group in almost all HRV parameters including SDNN, pNN50, RMSSD, VLF, LF, HF, and Total power. Among these, SDNN, VLF, and Total power were correlated with the (123)I-MIBG delayed heart to mediastinum ratio. CONCLUSION Impaired HRV was detected in patients with probable DLB. Non-invasive and routine electrocardiogram may have potential in differentiating DLB from AD.

Primary visual cortical metabolism and rapid eye movement sleep behavior disorder in dementia with Lewy bodies

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.

Effectiveness of ramelteon for treatment of visual hallucinations in dementia with Lewy bodies: a report of 4 cases.

CASE REPORT Dementia with Lewy bodies (DLB) is a neurodegenerative dementia disease characterized by the presence of core features including cognitive fluctuation, visual hallucinations (VHs), and parkinsonism and is categorized as Lewy body disease together with Parkinson disease (PD) in the established diagnostic criteria. Patients with DLB commonly show sleep disturbances such as excessive daytime sleepiness (EDS) and rapid eye movement sleep behavioral disorder (RBD) that is a suggestive feature. Choline esterase inhibitors (ChEIs) are the recommended first-line therapeutic agents for treatment of VHs in patients with DLB, although the Food and Drug Administration does not approve ChEIs for treatment of VHs. When ChEIs are ineffective for VHs, atypical antipsychotics such as quetiapine are the recommended second-line agents. However, patients with DLB frequently show hypersensitivity to antipsychotics. Ramelteon (RMT) is a melatonin agonist binding with melatonin 1 and 2 receptors and has been used for treatment of sleep disturbances. It has been reported that these melatonin receptors reduce in PD brains, and melatonin loading is an effective treatment for RBD in PD patients. Other research has shown that melatonin ameliorates EDS in PD patients. Here we report 4 cases of patients with DLB treated with RMT, producing apparent reductions in VHs as well as EDS and RBD. In addition to sleep disturbances, RMT may be effective for treatment of VHs in DLB. Visual hallucination was assessed using the ‘‘hallucination’’ subscore of Neuropsychiatry Inventory (NPI). Rapid eye movement sleep behavioral disorder was defined as abnormal, wild flailing 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. For assessment of EDS, the Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) were used. In addition, the Mini-Mental State Examination (MMSE), Unified Parkinson’s Disease Rating Scale (UPDRS) motor score, Barthel Index (Barthel), and Zarit Caregiver Burden Interview (Zarit) were used for assessment of cognitive functions, extrapyramidal signs, activities of daily living, and caregiver burdens, respectively. The 4 patients underwent brain MRI and F-fluorodeoxyglucose positron emission tomography as well as I-metaiodobenzylguanidine (MIBG) scintigraphy before administration of 8 mg/ d of RMT, because I-MIBG scintigraphy is useful for distinguishing Lewy body disease from other neurodegenerative disorders such as Alzheimer disease. Neuropsychiatric Inventory, ESS, PSQI, MMSE, UPDRS, Barthel, and Zarit were assessed after 2 and 8 weeks of RMT administration. This study was approved by the ethics committee of Juntendo Tokyo Koto Geriatric Medical Center. Written informed consent was obtained from all patients and their caregivers. The demographic data and assessment scores of the 4 patients after administration of RMT are presented in Table 1. These patients showed mild to moderate cognitive impairment and more than 2 core features including VHs, thereby meeting the diagnostic criteria of probable DLB. All patients showed EDS, whereas 2 of the 4 patients had RBD. In all patients, MRI revealed mild to moderate cortical atrophywithout prominent vascular changes, the glucose metabolic rate, measured by F-fluorodeoxyglucose positron emission tomography, was reduced in the occipital lobe and parietotemporal area, whereas I-MIBG scintigraphy demonstrated low myocardial uptake, supporting the diagnostic validity of DLB. In all patients, the hallucination subscore of NPI and scores of ESS and PSQI ameliorated after administration of RMT. The amelioration of the hallucination subscore of NPI occurred before simultaneously with that of ESS and PSQI scores. Visual hallucinations and RBD episodes disappeared after 8 weeks of RMT administration. After administration of RMT, total NPI and Zarit scores also ameliorated, indicating other psychiatric symptoms such as agitation and anxiety, and caregiver burdens improved. The scores of MMSE, Barthel, and UPDRS did not change significantly, indicating cognitive functions, daily living, and extrapyramidal signs did not deteriorate.

Early differential diagnosis between Alzheimer's disease and dementia with Lewy bodies: Comparison between 18F-FDG PET and 123I-IMP SPECT

Both (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and (123)I-iodoamphetamine (IMP) single-photon emission computed tomography (SPECT) have been used for the differential diagnosis of Alzheimers disease (AD) and dementia with Lewy bodies (DLB). Less information is available, however, regarding the differential diagnosis of mild cognitive impairment (MCI) due to AD and MCI due to DLB. We examined nine AD patients (AD group), nine DLB patients (DLB group), eight MCI due to AD patients (MCI-AD group), and nine MCI due to DLB patients (MCI-DLB group) with FDG PET and IMP SPECT using a well-characterized normal database and a stereotactic extraction estimation method. In the AD and DLB groups, receiver operating characteristic (ROC) analysis in the occipital regions showed significant accuracy of both FDG PET and IMP SPECT for the differential diagnosis. In the MCI-AD and MCI-DLB groups, ROC analysis showed significant accuracy of only FDG PET for the differential diagnosis. Both FDG PET and IMP SPECT would be useful for the differential diagnosis between AD and DLB. For the differential diagnosis of MCI-AD versus MCI-DLB, FDG PET would be more useful than IMP SPECT.

A Case of Parkinson Disease With Both Visual Hallucination and Pain Improved by Gabapentin.

ObjectivesVisual hallucinations (VHs) and pain are common non-motor symptoms in Parkinson disease (PD). Although dopaminergic dysfunction has traditionally been considered as the principal cause of these symptoms, the detail mechanisms are still unclear. Conventional treatment for VH, decrease of dopamine agonists, and use of antipsychotic medications often lead to an exacerbation of motor symptoms and excessive sedation. Gabapentin (GPT) is an antiepilepsy drug, which affects the glutamic acid neuron system and the &ggr;-amino butyric acid neuron system. It is also known to have an analgesic effect. Here, we report a case of PD in which GPT improved both VH and pain without any adverse effects. MethodsThis study is a case report. ResultsThe subject is an 81-year-old Japanese man who was diagnosed with PD at the age of 67 years. His Hoehn and Yahr staging scale was IV. He developed VH of insects and also experienced pain, which is, as he described, caused by these insects invading his body. Despite the general treatments, VH and pain persisted. Moreover, exacerbation of motor symptoms and excessive sedation hindered a further attempt. Gabapentin was administered to ease his pain. After that, not only pain but also VH disappeared without any adverse effects. ConclusionsThe positive outcomes of GPT on VH and pain without any adverse effects may offer us a useful alternative treatment for PD. Further experience and study are needed to prove the efficacy of this agent.