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Objectives To evaluate the long-term efficacy and safety of zonisamide, an antiepileptic agent, in dementia with Lewy bodies (DLB). Design Phase three clinical trial with 12 week, randomized, placebo-controlled, double-blind, and subsequent 40 week, open-label, extension periods. Setting A total of 109 centers in Japan between April 2015 and November 2017. Participants Outpatients diagnosed with probable DLB. Intervention Outpatients were randomly assigned to receive placebo (P) or zonisamide 25 or 50 mg/day for 12 weeks. In the subsequent open-label 40 week period, all patients initially received zonisamide 25 mg/day for at least 2 weeks followed by optional flexible dosing with zonisamide 25 or 50 mg/day for the remaining period. Measurements The primary outcome was efficacy on motor symptoms, assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, over the total 52 week trial period. Effects on behavioral and psychological symptoms of dementia and cognitive function, and safety were also evaluated. Results In total, 335 patients were included in the long-term analysis: 106, 117, and 112 in the P-, 25mg-, and 50mg-Flex groups, respectively. UPDRS-III score continued to improve for an additional 12 to 16 weeks in the open-label period (mean [standard deviation] change from baseline at Week 28: −5.1 [7.3] and −6.3 [8.2] in the 25mg- and 50mg-Flex groups) and remained almost constant thereafter. No unexpected neurological or psychiatric adverse events occurred, and no adverse events increased in incidence in the open-label period. Conclusions Long-term treatment with zonisamide was well tolerated and yielded sustained improvement in motor symptoms. Trial registration JapicCTI-152839 (Registered on 9 March 2015) https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152839

Background and purposeWe previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD.MethodsWe undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline.ResultsSixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline.ConclusionsOur follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested.Trial registration numberUMIN00003419.

Introduction Zonisamide is approved in Japan for treating motor dysfunction in Parkinson's disease, and might also be effective for parkinsonism in patients with dementia with Lewy bodies (DLB). Our study evaluated the safety and efficacy of zonisamide for treating parkinsonism in patients with DLB. Methods This multicenter, randomized, double-blind, phase 3 trial was conducted in Japan between April 2015 and November 2017. Following a 4-week run-in period, outpatients diagnosed with probable DLB who had developed parkinsonism were randomized to receive oral zonisamide (25 or 50 mg/day) or placebo for 12 weeks, followed by a 40-week open-label extension. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score at Week 12. Results Of 351 patients randomized, 346 (mean age, 77.2 years; 188 males) were included in the modified intention-to-treat population. At Week 12, the group difference (least squares mean ± SEM) for changes from baseline (vs placebo) in UPDRS part III total score was −2.7 ± 0.9 (95% confidence interval [CI]: −4.4, −0.9, P = 0.005) in the zonisamide 25-mg group and −2.6 ± 0.9 (95% CI: −4.4, −0.8, P = 0.005) in the zonisamide 50-mg group. Adverse events were reported in 47.1%, 48.7%, and 54.5% of patients in the placebo and zonisamide 25- and 50-mg groups, and led to treatment discontinuation in 5.0%, 4.3%, and 9.8% of patients, respectively. Conclusion Daily administration of 25- or 50-mg zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated in patients with DLB.

The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies.

ObjectiveTo investigate whether increasing plasma donepezil concentration further improves cognitive function and neuropsychiatric symptoms without compromising safety in patients with dementia with Lewy bodies (DLB).MethodsWe analyzed data from a 12-week phase 3 trial of donepezil (5 and 10mg/day) in patients with DLB. The contribution of factors affecting plasma donepezil concentration was evaluated using multivariate regression analysis. The relationships between plasma donepezil concentration and efficacy (cognitive function as measured by the Mini-Mental State Examination [MMSE], hallucinations and cognitive fluctuation), or safety (blood pressure, pulse rate, body weight, and parkinsonism as measured by the Unified Parkinson's Disease Rating Scale part III) were assessed by scatterplots and Pearson correlation.ResultsThe data of 87 patients were used in the analyses. Plasma donepezil concentration increased proportionally with increasing dose from 5 to 10mg/day. The dose (contribution rate: 0.39, p

Epilepsy with the main symptom of amnesia is known as transient epileptic amnesia (TEA). Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. The concept that Lewy body disease includes Parkinson's disease with dementia and dementia with Lewy bodies was proposed in the 2005 revision of the Clinical Diagnostic Criteria. Here, we describe a woman with cognitive impairment, olfactory dysfunction, and reduced 123 I-meta-iodobenzylguanidine uptake on myocardial scintigraphy. The patient and her family and friends were unaware of parkinsonism, visual hallucinations, or epilepsy for a long period. After syncope occurred twice within a short interval, electroencephalography revealed sharp waves from the bilateral frontal to parietal lobes, indicating a diagnosis of TEA. The present case prompted us to compare the symptoms of TEA with the clinical diagnostic criteria for dementia with Lewy bodies, revealing their similarities. We also discuss whether Lewy body disease may cause TEA rather than having an incidental association with it.

Background/Aims: Based on Mini-Mental State Examination (MMSE) subitem scores, in dementia with Lewy bodies (DLB), we aimed to delineate features of cognitive impairment, identify cognitive domains improved by donepezil, and define a pretreatment cognitive profile likely to benefit from donepezil. Methods: Pooled data were used from two randomized controlled trials of donepezil in DLB (n = 235). Baseline MMSE subitem scores were calculated for all patients. Mean changes in subitem scores at week 12 were compared between the placebo and the active group. Finally, the subgroup identification based on differential effect search (SIDES) method was applied. Results: Baseline subitem scores were relatively low for serial 7's, delayed recall, and copying. Significant improvement by donepezil was found for orientation, serial 7's, repetition, 3-step command, and copying. The subgroup with pretreatment scores of serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 were the best responders. MMSE change in subgroups increased as more of these three conditions were fulfilled. Conclusion: Cognitive domains characteristically impaired in DLB are particularly improved by donepezil. The number of fulfilled conditions for serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 (likely to benefit score) may predict the response to donepezil in DLB patients.

Diffuse neurofibrillary tangles with calcification (DNTC) is a rare, pre-senile type of dementia. The term 'DNTC' was initially proposed by Kosaka in 1994. Although 26 autopsies and 21 clinical patients with DNTC have been described in Japan to date, DNTC has rarely been reported in the European and North American published work. We speculate that DNTC has been overlooked in other countries. Herein, we review all known reports of DNTC in Japan and propose clinical diagnostic criteria for DNTC.

Background As with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dose-dependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose. Methods The present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy. Results The Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. High-dose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms. Conclusions We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.

Background/Aims: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Methods: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. Results: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. Conclusion: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.

The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas-Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4R) tau, but some of the NFTs were positive for 3-repeat (3R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3R tau in NFTs.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

ObjectiveTo investigate the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB).MethodsThis phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (placebo or zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symptoms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed.ResultsOverall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was significantly greater in the zonisamide 50 mg group compared with placebo (between-group difference −4.1; 95% confidence interval −6.8 to −1.4; p = 0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups.ConclusionZonisamide (adjunctive to levodopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms.Clinical trial registrationJapicCTI-122040.Classification of evidenceThis study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB.

"Dementia with Lewy bodies (DLB)" was proposed at the first international workshop in 1995. It has received much attention since we had proposed "Lewy body disease" in 1980 and "diffuse Lewy body disease" in 1984. In the CDLB guidelines, which were reported in 1996, the clinical and pathological diagnostic criteria for DLB were shown for the first time. At present, DLB as well as Alzheimer's disease (AD) and vascular dementia (VD) are known as the three major dementing illnesses. The second international workshop was held in 1998, and the third in 2003. One of the authors, K. Kosaka, presented a paper on DLB at each international workshop, based on series of our papers which we had reported since 1976. The revised CDLB guidelines will be reported soon. In addition, the fourth international workshop on DLB will be held by Kosaka in Yokohama in 2007. In this article, we review the history, the clinical, therapeutic, neuropathological, neurochemical and molecular biological issues, based on our previous papers and other important reports on DLB.

Rapid economic growth sometimes intensifies people's frustration. In this article, we attempt to formulate this kind of paradox of economic growth, and to explain theoretically how economic growth increases people's dissatisfaction by way of the notion of relative deprivation by employing the theoretical framework of Yitzhaki's relative deprivation index. We introduce the problem of the China puzzle as the latest case of the paradox. Then, we introduce the definition of Yitzhaki's index of relative deprivation, and use this to explain the China puzzle. Besides, through a theoretical examination of Yitzhaki's index, we propose a proposition proving that an increase of relative deprivation in the society can occur even when the amount of wealth increases and the degree of inequality reduces.

We proposed the term 'Lewy body disease' (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brainstem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. LBD has neuropathological characteristics whereby numerous Lewy bodies are present in the central and sympathetic nervous systems, and it is a type of alpha-synucleinopathy because the main component of Lewy body is alpha-synuclein. In this paper we explain the most recent concept of LBD from the historical viewpoint.

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.

In 1976 we reported our first autopsied case with diffuse Lewy body disease (DLBD), the term of which we proposed in 1984. We also proposed the term “Lewy body disease” (LBD) in1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term to include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), which was proposed in 1996 on the basis of our reports of DLBD. DLB is now known to be the second most frequent dementia following Alzheimer’s disease (AD). In this paper we introduce our studies of DLBD and LBD.

We proposed the term “Lewy body disease” (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type, and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term including Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB).

Behavioral and psychological symptoms of dementia (BPSD) are observed in all forms of dementia. We discuss representative forms of BPSD such as hallucination and delusion, depression, and rapid eye movement (REM) sleep behavior disorder (RBD) observed in patients with dementia with Lewy bodies (DLB). The most representative BPSD for DLB is visual hallucination. McKeith et al. reported that 80 % of DLB cases involved visual hallucination. Delusions occur more frequently in DLB, compared with Alzheimer’s disease (AD). These in the patients with DLB are characterized by delusional misidentification either as a continuation of visual hallucinations or related to delusions resulting from visual misidentification of places, people, or surroundings. Depression is one of the first symptoms of DLB and is listed in the CDLB guidelines as one of the supportive features. One suggestive sign of DLB is rapid eye movement (REM) sleep behavior disorder (RBD), which is significantly more common in the patients with DLB than other forms of neurodegenerative dementia. RBD also occurs earlier than cognitive dysfunction and primary core symptoms such as parkinsonism and visual hallucination.

Objective The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of 123I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Methods Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and 123I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline 123I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. Results Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). Conclusions 123I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.

Background: This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies. Methods: Sixty-three dementia with Lewy bodies patients with probable BPSD (M : W, 30 : 33; mean age, 78.2 ± 5.8 years) were enrolled and treated with YKS for 4 weeks. Results: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P < 0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P= 0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n= 23; mean decrease, 14.4; P < 0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n= 22; mean decrease, 8.2; P < 0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (

123I-metaiodobenzylguanidine cardiac scintigraphy (MIBG) is a useful imaging technique for the diagnosis of dementia with Lewy bodies (DLB). However, MIBG has a serious disadvantage in that it demands a long examination time. The objective of this study was to evaluate statistically the usefulness of the heart/mediastinum ratio (H/M) from the early phase of MIBG for the differential diagnosis of DLB. In total, 113 patients were examined, including 32 non-DLB (19 with Alzheimer's dementia) and 79 DLB patients. The mean early-H/M ratio was 2.83 in the non-DLB group and 1.95 in the DLB group. The mean delayed-H/M ratio was 3.0 in the non-DLB group and 1.76 in the DLB group. With a cutoff point of 2.27 on early images, the sensitivity, specificity, and diagnostic accuracy were 65%, 94%, and 73%, respectively, and the area under the curve was 0.82, indicating moderate accuracy. This analysis indicates that images from the early phase of MIBG alone are sufficient for the differential diagnosis of Alzheimer's disease and DLB.

We examined psychiatric symptoms in eight cases with dementia with Lewy bodies (DLB), which included visual hallucination of persons or small animals, visual illusion, metamorphosia, leibhaftige Bewusstheit, personal or topographical misidentification, Capgras' syndrome and reduplicative paramnesia as well as depressive state and delusion of persecution. These psychiatric symptoms are identical to those of levodopa-induced psychosis, although these symptoms appeared before medication with anti-Parkinson drugs. The hypersensitivity of the dopamine receptor in the meso-limbic dopaminergic system has been presumed in levodopa-induced psychosis. We previously showed disturbance of the nigro-amygdaloid dopaminergic connections in DLB brains on pathological studies. Hypoperfusion or glucose hypometabolism in the occipital lobe has been demonstrated in DLB patients using SPECT or PET. The amygdala has reciprocal connections with the visual cortex in the occipital lobe. From these findings, it is supposed that the disturbance of the nigro-amygdaloid connections induces hypersensitivity of the dopamine receptor in the amygdala, causing psychiatric symptoms with dysfunction of the visuo-amygdaloid connections.

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aβ immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aβ immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.

Background: In out-patient clinics, having simple procedures to check for signs of dementia is invaluable. In the present study, we evaluated the imitation of hand gestures to detect visuomotor deficits in dementia in clinical practice. Methods: In all, 1219 subjects were enrolled in the present study, including 497 with Alzheimer's disease (AD), 98 with dementia with Lewy bodies (DLB), 71 with other types of dementia diseases, 175 with a Clinical Dementia Rating (CDR) of 0.5, and 378 normal controls. All subjects were aged 65 years or older. Subjects were recruited from 10 clinics and two communities. Visuomotor function was evaluated by the Yamaguchi fox–pigeon imitation test (YFPIT), which consists of a simple one-handed sign for ‘fox’ and a complex two-handed sign for ‘pigeon’, a rapid, game-like test with low psychological burden. Results: The success rate (successful/total) for imitating the ‘pigeon’ hand gesture was reduced as the severity of the dementia increased: 85.7% in normal controls, 60.6% in CDR 0.5 (mild cognitive impairment), 39.2% in CDR 1 (mild dementia), 21.2% in CDR 2 (moderate dementia), and 5.7% in CDR 3 (severe dementia). The success rate for imitating the ‘pigeon’ hand gesture was higher in patients with DLB than AD within the CDR 1 group (51.2% vs 35.4%, respectively), but lower for patients with DLB than AD within the CDR 2 group (12.5% vs 24.4%, respectively). The success of imitating the hand gesture for ‘fox’ was similar for patients with AD and DLB. Of those subjects who failed to imitate the hand gesture for ‘pigeon’, 49.5% of those with AD showed the palm–palm pattern (both palms facing outward), suggesting deficits of perspective conversion from the first-person to the third-person. Conversely, 52.8% of patients with DLB showed a dorsum–dorsum pattern (both dorsa facing outwards), suggesting deterioration of visual attention and recognition. Conclusion: In conclusion, the YFPIT is a useful test to detect visuomotor deficits in dementia that can differentiate between AD and DLB.

There is emerging evidence implicating a role for the autophagy-lysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support apotential role for the autophagy-lysosome pathway in the pathogenesis of DLB.

To disclose the neuropathological progression course of Machado-Joseph disease (MJD), magnetic resonance imaging (MRI) findings of six genetically confirmed MJD cases (four males and two females, including an autopsied female, all unrelated to one another) were further investigated on neurodegeneration. Brain MRI studies were repeated in all cases at different stages of the disease. Ages at the first MRI study ranged from 47 to 65 years (55.2 ± 7.1), with observation periods from 4.5 to 10.6 years (6.95 ± 2.48). We paid particular attention to two types of previously reported MRI findings detectable using T2-weighted images. One is located just outside the internal capsules, and another in the pons. A linear high-intensity change along the internal capsules was detected in all cases, and showed progression during the observation period. A comparison between MRI and autopsy findings suggested that the lesion might reflect degeneration with neuronal loss, astrocytosis, and gliosis in the internal segment of the globus pallidus. A cross-shaped high-intensity change in the pons was well advanced but still incomplete in all cases. In this region, pontine transverse fibers were atrophic, while longitudinal fibers remained intact. Pontine nuclei showed apparent nerve cell loss, and the remaining cells had many 1C2-positive intranuclear inclusions. Since these findings were detected both by lifetime images and by postmortem examination, MRI intensity changes could track the progression of neurodegeneration. Based on a comparison between MRI findings and neuropathology, the degeneration of an internal segment of the globus pallidus (one of the pathological features of MJD) had progressed following the initial symptoms.