Long-Term Efficacy and Safety of Zonisamide for Treatment of Parkinsonism in Patients With Dementia With Lewy Bodies: An Open-Label Extension of a Phase three Randomized Controlled Trial.

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.

123I-MIBG myocardial scintigraphy for the diagnosis of DLB: a multicentre 3-year follow-up study.

BACKGROUND AND PURPOSE: We 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. METHODS: We 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. RESULTS: Sixty-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. CONCLUSIONS: Our 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 NUMBER: UMIN00003419.

Similarity of symptoms between transient epileptic amnesia and Lewy body disease.

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.

Pretreatment Cognitive Profile Likely to Benefit from Donepezil Treatment in Dementia with Lewy Bodies: Pooled Analyses of Two Randomized Controlled Trials.

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.

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development.

BACKGROUND/AIMS: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. METHODS: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. RESULTS: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. CONCLUSION: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.

Diffuse neurofibrillary tangles with calcification (Kosaka-Shibayama disease) in Japan.

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.

Increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with Lewy bodies.

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.

Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies.

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.

An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years.

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.

Latest concept of Lewy body disease.

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.

Lewy body disease and dementia with Lewy bodies.

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) 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 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.

Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1.

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.

Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial.

OBJECTIVE: Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial. METHODS: One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III. RESULTS: Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p < 0.001 for each); 3 mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10 mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups. INTERPRETATION: Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated.

Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study.

BACKGROUND/AIMS: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB). METHODS: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout. RESULTS: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear. CONCLUSION: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.

Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan, a traditional Japanese medicine.

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 (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed. CONCLUSION: YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.

Gray matter lesions in Nasu-Hakola disease: a report on three autopsy cases.

Nasu-Hakola disease is an autosomal recessively inherited disease characterized by lipomembranous polycystic osteodysplasia and sclerosing leukoencephalopathy. While white matter lesions prominent in the brain have been reported in the literature, gray matter lesions have not received particular attention. In this study, we examined three autopsy cases of Nasu-Hakola disease in order to focus specifically on gray matter lesions. The ages at onset of the three cases were 20, 23 and 29 years, and the disease durations were 29, 19 and 8 years, respectively. In addition to characteristic degeneration in the cerebral white matter, such as demyelination with conspicuous fibrillary gliosis and axonal changes, all three cases showed overt pathology in the gray matter. Neuronal loss with gliosis in the thalamus (particularly in the dorsomedial nucleus and anterior nucleus), caudate nucleus, putamen and substantia nigra was prominent in all cases, and the severity corresponded to the disease duration. The cerebral cortices were relatively preserved in all cases. One case showed neuronal loss and gliosis in the gray matter of the hippocampus, possibly due to repeated episodes of epileptic convulsions. These gray matter pathologies are considered to be responsible for some of the clinical manifestations of the disease, including extrapyramidal symptoms.

Yamaguchi fox-pigeon imitation test (YFPIT) for dementia in clinical practice.

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.

Decreased ventilatory response to hypercapnia in dementia with Lewy bodies.

A systematic autonomic dysfunction observed among patients with dementia with Lewy bodies (DLB) has recently attracted close attention. Here, we compare cardiovascular and pulmonary autonomic functions among patients with DLB, patients with Alzheimer's disease, and healthy control subjects. All 15 DLB patients demonstrated severely low ventilatory response to hypercapnia, whereas none of the other subjects demonstrated abnormal results. The majority of the DLB patients showed impaired heart rate variability, low uptake on (123)I-metaiodobenzylguanidine myocardial scintigraphy, and orthostatic hypotension. Ventilatory response to hypercapnia as a marker of respiratory autonomic function is a promising diagnostic tool for DLB.

The first autopsied case of diffuse Lewy body disease (DLBD): re-examination by recent immunostaining methods: The 50th Anniversary of Japanese Society of Neuropathology.

Materials from our first autopsied case of diffuse Lewy body disease (DLBD), that was originally reported in 1976, were re-examined using recent immunohistochemical methods. Lewy pathology consisting of Lewy bodies and Lewy neurites appeared much more marked with alpha-synuclein immunostaining than had been detected with classical stainings. This case and our other similar cases prompted us to propose the terms "Lewy body disease" in 1980 and "diffuse Lewy body disease" in 1984. We also reported in 1990 that DLBD was classified into two forms: a pure form and a common form. Based on these studies the term "dementia with Lewy bodies (DLB)" was proposed in 1996. Since 1980, we have insisted that DLB, Parkinson disease (PD), and PD with dementia (PDD) should be understood within the spectrum of Lewy body disease. This insistence has been recently accepted by the International Workshop and the International Working Group on DLB and PDD in 2005 and in 2006, respectively.