Structural Transformation of Azonia[5]helicene Photoproduct via Reaction Field Function of Layered Inorganic Material.

In an attempt to generalize "on surface synthesis", which has unique potential in the area of organic synthesis, the focus was placed on layered silicates having a highly flat surface. The photoreaction of (±)-13-bromo-6a-azonia[5]helicene (AHHBr) and (±)-2-bromo-13-methyl-6a-azonia[5]helicene (AHBrMe) in solution and within the layers was examined. In the case of AHBrMe, the photoproduct was different from that in solution. 1H nuclear magnetic resonance (NMR), Fourier transform-infrared spectroscopy (FT-IR), and electrospray ionization-mass spectrometry (ESI-MS) measurements revealed that the photoproduct obtained within the layers was a benzo-perylene molecule with a completely flat lactone structure (AL). This study is the first example of the successful conversion of a chemical reaction path due to the steric effect of the flat surface of layered silicate.

Senescence recovering by dual drug-encapsulated liposomal nanoparticles for large-scale human cell expansion.

Although regenerative therapy and bioartificial tissues and organs require a sufficient number of human cells, current cell expansion processes are accompanied by accumulation of senescent cells that are related to deterioration of cellular functions and induction of senescence-associated secretory phenotype (SASP). Therefore, suppression of replicative senescence during expansion is one of the crucial issues for dissemination of regenerative medicine. We herein developed dual drug-encapsulated liposomal nanoparticles (LNPs) to suppress cellular senescence in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and natural killer (NK) cells by removal of dysfunctional mitochondria from the senescent cells. We found that LNP treatment reduced senescent makers; downregulation of p21 expression and reduction of SA-ß-Gal activity in both cells provably due to mitophagy reactivation in the cells. Moreover, SASP secretion in hAT-MSCs and tumor cytotoxicity in NK cells were also improved upon LNP treatments. These findings may contribute to the production of highly effective expanded cells for regenerative medicine and bioartificial tissues and organs.

[Surgical Treatment of Congenital Absence of the Pericardium Found by Chance at Pulmonary Surgery:Report of a Case].

Absence of the pericardium is generally asymptomatic rare congenital disorder. However, it may be life-threatening problem due to cardiac deviation or herniation after the pulmonary resection. We described a case of complete defect of the pericardium found at surgery for metastatic lung cancer. Since the left lower lobectomy was necessary, the pericardium was reconstructed with an ePTFE sheet. Postoperative course was uneventful without any symptoms at two years post-surgery.

Evaluating depression in cognitively healthy elderly people by using Mini-Mental State Examination.

AIM: We examined a method for evaluating depression with the Mini-Mental State Examination in cognitively healthy elderly people and employed the projective perspective. METHODS: In MMSE three groups-normal, depressed tendency, and depressed-completed the Mini-Mental State Examination (MMSE) and a Japanese version of the 15-item Geriatric Depression Scale. The Mini-Mental State Examination evaluated individuals' writing based on a sentence, the number of written words, and sentence content; it also assessed their copying of drawn figures. RESULTS: In the depressed group, the proportion corresponding to the characteristics of (i) to (iii) was higher than in the other two groups: (i) the calculation score was 0 or 1; (ii) subjects scored above the median in sentence writing relative to similar subjects with the same language and clinical setting; and (iii) subjects expressed feelings in their writing. One point was given for each characteristic, and we calculated the sum. Depressed subjects had a score ≥2. CONCLUSIONS: This evaluation method can differentiate depressed subjects with high accuracy (sensitivity: 77.8%, specificity: 76.4%) without placing an extra burden on the subjects.

123I-FP-CIT SPECT findings and its clinical relevance in prodromal dementia with Lewy bodies.

PURPOSE: Evidence for the prodromal stage of dementia with Lewy bodies (DLB) is very limited. To address this issue, we investigate the 123I-FP-CIT SPECT measure of dopamine transporter binding finding and its clinical relevance. METHODS: We enrolled subjects into a prodromal DLB group (PRD-DLB) (n = 20) and clinical DLB group (CLIN-DLB) (n = 18) and compared these groups with an Alzheimer's disease control group (AD) (n = 10). PRD-DLB was defined as patients having the non-motor symptoms associated with Lewy body disease (LBD) [i.e. REM sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, and depression] and showing characteristic diffuse occipital hypometabolism in 18F-FDG PET. CLIN-DLB was defined as patients fulfilling the established criteria of probable DLB. Striatal specific binding ratio (SBR) of 123I-FP-CIT SPECT was used for objective group comparisons. The correlations between SBR and cognitive function (MMSE), motor symptoms (UPDRS3), and duration of LBD-associated non-motor symptoms were compared between the two DLB groups. RESULTS: Mean SBR scores of both PRD-DLB and CLIN-DLB were significantly lower than those of AD. No correlation was found between SBR and MMSE scores. Both in the CLIN-DLB and total DLB groups, SBR scores were negatively correlated with UPDRS3 scores, whereas no correlation was found in PRD-DLB. Among the LBD-related non-motor symptoms, duration of olfactory dysfunction, and RBD demonstrated negative correlation with SBR scores in PRD-DLB. CONCLUSION: 123I-FP-CIT SPECT may play a role for detecting DLB among the subjects in prodromal stage. During this stage, long-term olfactory dysfunction and/or RBD may indicate more severe degeneration of the nigro-striatal dopaminergic pathway.

CD163-Positive Macrophages Within the Tumor Stroma Are Associated With Lymphangiogenesis and Lymph Node Metastasis in Oral Squamous Cell Carcinoma.

PURPOSE: Increasing evidence shows that tumor stromal components, particularly tumor-associated macrophages (TAMs), play an important role in the tumor progression of various solid malignant tumor types. However, their roles in oral squamous cell carcinoma (OSCC) have not been fully elucidated. MATERIALS AND METHODS: Seventy human tongue OSCC samples were analyzed in the present study. Immunohistochemistry was used to investigate the correlations between the densities of CD68-, CD163-, and CD204-positive TAMs and clinicopathologic parameters. Lymphatic vessel density (LVD) was estimated using the D2-40 antibody. In vitro studies also were conducted to investigate the effect of conditioned medium (CM) derived from OSCC cell lines on cytokine and chemokine expression in RAW264.7 mouse monocytic leukemia cells. RESULTS: Increased densities of CD68-, CD163-, and CD204-positive TAMs were significantly correlated with lymph node metastasis (P = .035, .0082, and .038, respectively). Higher LVD occurred considerably more frequently in patients with nodal metastasis than in those without such metastasis. Moreover, LVD was considerably increased in patients with higher CD163-positive TAM densities. Studies using immunofluorescence showed that vascular endothelial growth factor (VEGF)-C was expressed in 52 of 70 patients with CD163-positive TAMs (74.2%). Moreover, CM derived from OSCC cell lines stimulated the expression of Il-10, Ccl22, Vegf-a, and Vegf-c in RAW264.7 cells; however, Il-12p35 expression levels were not changed. CONCLUSION: CD163-positive TAMs promote lymphangiogenesis through VEGF-C expression, which contributes to regional lymph node metastasis in OSCC.

Establishment of a xenograft model to explore the mechanism of bone destruction by human oral cancers and its application to analysis of role of RANKL.

BACKGROUND: The molecular mechanism underlying bone invasion caused by oral squamous cell carcinoma (OSCC) is not well understood. To elucidate the molecular mechanism, the development of more suitable xenograft models mimicking human mandibular bone destruction by OSCC has been required. MATERIALS AND METHODS: Human OSCC cell lines, HSC3, HSC3-C1, and HSC3-R2, were injected in the periosteal region of the mandible in athymic mice, and the bone destruction was analyzed. Receptor activators of nuclear factor κ-B ligand (RANKL) mRNA and protein expression levels were measured in the OSCC cell lines. Antibody that specifically neutralizes mouse RANKL and human RANKL, respectively, was injected into HSC3-cell-transplanted mice. RESULTS: Transplantation of HSC3 cells induced mandibular bone destruction. Histological examination revealed numerous osteoclasts on the bone destruction surface. Fibroblastic cell intervention between the cancer nests and resorbing bone surface was observed in a similar fashion to those observed in human OSCC cases. The number of osteoclasts and fibroblasts was significantly correlated. Bone destruction induced by the transplantation of HSC3 cells was reduced by injection of an antibody that specifically neutralizes mouse RANKL. Transplantation of HSC3-R2 cells, which overexpresses RANKL, induced advanced bone destruction compared to that of HSC3-C1 cells, which only overexpress the empty vector. CONCLUSIONS: We established a useful xenograft model for investigating the molecular mechanism underlying the bone destruction induced by OSCC in the jaw. This model will be used to investigate the precise roles of several cytokines synthesized by both cancer cells and fibroblastic cells in OSCC-associated bone destruction in the jaw.

Cognitive dysfunction in patients with very mild Alzheimer's disease and amnestic mild cognitive impairment showing hemispheric asymmetries of hypometabolism on ¹8F-FDG PET.

OBJECTIVE: We investigated cognitive dysfunction in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) who present hemispheric asymmetries of cerebral metabolic rate of glucose (CMRglc) decrease on (18) F-fluorodeoxyglucose positron emission tomography. METHODS: Based on the hemispheric asymmetries of CMRglc decrease in the posterior cingulate cortex, precuneus, and parietotemporal cortex, the patients were divided into three groups (a left-dominant hypometabolism group, a right-dominant hypometabolism group, and a non-dominant hypometabolism group). CMRglc decrease in the whole brain was controlled among the three groups. All the patients underwent mini-mental state examination (MMSE), Wechsler Memory Scale-Revised (WMS-R), and Wechsler Adult Intelligent Scale-Third (WAIS-III). RESULTS: There were no significant differences in MMSE and WAIS-III scores among the three groups. In WMS-R, the results indicated that the left-dominant group demonstrated significantly lower scores in verbal memory than the other two groups. Furthermore, the left-dominant group had a greater tendency to be diagnosed with AD rather than aMCI. CONCLUSIONS: Patients with AD and aMCI showing left-dominant hypometabolism tend to show severer impairment in verbal memory function and to be diagnosed with AD dementia.

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

OBJECTIVES: It is well known that Alzheimer's 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 [(18)F]fluoro-d-glucose ((18)F-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. METHODS: Twenty-three DLB patients, 10 AD patients, and 11 controls underwent (18)F-FDG PET scans. According to the degree of hypometabolism in the parietal/precuneus regions, representing the AD-like metabolic pattern, 12 patients were placed in the DLB-AD(+) group and 11 patients were placed in the DLB-AD(-) group. The demographics and clinical variables were compared among the four groups. RESULTS: In addition to the parietal/precuneus regions, the DLB-AD(+) group exhibited significantly greater posterior cingulate hypometabolism than the DLB-AD(-) group, although occipital metabolism did not differ. The prevalence of visual hallucinations and extracampine hallucinations, and the Bender-Gestalt test score were significantly higher in the DLB-AD(+) group than the DLB-AD(-) group, although there were no differences in the demographics and other examined clinical variables between the two DLB groups. These clinical differences were absent in the DLB-AD(-) group, AD group, and controls. CONCLUSIONS: Parietal/precuneus hypometabolism may be associated with clinical characteristics in DLB patients. Further multiple imaging modalities that are sensitive to AD-type pathology are needed to reveal the neurobiological basis of the AD-like metabolic pattern.

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.

RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer.

The molecular mechanisms underlying bone destruction by invading oral cancer are not well understood. Using IHC, we demonstrated that receptor activator of nuclear factor-κB ligand (RANKL)-positive fibroblasts and cancer cells were located at sites of bone invasion in human oral cancers. HSC3 and HO-1-N-1, human oral cancer cell lines, expressed RANKL and stimulated Rankl expression in the UAMS-32 murine osteoblastic cell line. We discriminated the roles of RANKL synthesized by stromal cells and cancer cells in cancer-associated bone resorption by using species-specific RANKL antibodies against murine RANKL and human RANKL, respectively. Osteoclastogenesis induced by the conditioned medium of HSC3 and HO-1-N-1 cells in a co-culture of murine bone marrow cells and UAMS-32 cells was inhibited by the addition of antibodies against either mouse or human RANKL. HSC3-induced bone destruction was greatly inhibited by the administration of anti-mouse RANKL antibody in a xenograft model. HO-1-N-1-induced bone destruction was inhibited by the administration of either anti-mouse or anti-human RANKL antibody. Bone destruction induced by the transplantation of human RANKL-overexpressing cells (HSC3-R2) was greatly inhibited by the injection of anti-human RANKL antibody. The present study revealed that RANKL produced by both stromal and cancer cells is involved in oral cancer-induced osteoclastic bone resorption. These results provide important information for understanding the cellular and molecular basis of cancer-associated bone destruction and the mechanism of action underlying RANKL antibody (denosumab) therapy.

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

AIM: Significant glucose hypometabolism in the primary visual cortex (PVC) is considered to support a diagnosis of dementia with Lewy bodies (DLB), but its relationship to the clinical features remains unknown. The purpose of this study was to assess the association between the metabolic pattern and clinical variables in DLB. METHODS: A total of 27 DLB patients who underwent [18F]fluoro-d-glucose (18F-FDG) positron emission tomography scans were examined. Demographics and clinical variables were compared between patients with and without glucose hypometabolism in the PVC. The correlations between the cerebral metabolic rate of glucose in the PVC and clinical variables were also investigated. RESULTS: Only the onset age of probable rapid eye movement sleep behavior disorder (RBD) was significantly different between patients with and withoutglucose hypometabolism in the PVC, being younger in patients with the metabolic pattern; there were no other differences in clinical variables. The onset age of probable RBD was significantly correlated with the cerebral metabolic rate of glucose in the PVC. CONCLUSIONS: Glucose hypometabolism in the PVC provides a potential mechanism for the link between antecedent RBD and the subsequent development of dementia in DLB patients. Glucose hypometabolism in the PVC may represent the effect of the pathophysiological process of DLB on RBD rather than a distinct condition in the disease progression. The physiological aspects of the link between this metabolic pattern and the onset of RBD remain unclear.

Three presenile patients in which neuropsychological and neuroimaging examinations suggest possible progression to dementia with Lewy bodies.

We report three presenile patients who were initially suspected of having Alzheimer's disease (AD) or being in the prodromal stage of AD, regardless of visuoperceptual dysfunctions in daily living, because they lacked the core features and prodromal non-motor symptoms of dementia with Lewy bodies. Subsequently, progression to dementia with Lewy bodies was suspected based on neuropsychological and neuroimaging findings; additionally, one of the three patients suffered from visual hallucinations. Neuropsychological examinations such as subjective contours, cube copying and block design in the Wechsler Adult Intelligence Scale-III revealed visuoperceptual dysfunction in all three patients even when other cognitive functions were rather preserved. Brain magnetic resonance imaging revealed no significant brain atrophy, including in the parieto-occipital area and the hippocampus, while brain (18)F-fluorodeoxyglucose positron emission tomography demonstrated right dominant metabolic reductions in the occipital lobe, including the primary visual cortex, in all three patients. We suggest the possibility of progression to dementia with Lewy bodies, but not AD or posterior cortical atrophy. Regardless of the presence of core features and prodromal non-motor symptoms, this progression is suggested when there are difficulties only in higher-level visual processing such as subjective contours and block design in the Wechsler Adult Intelligence Scale-III, no significant atrophy of the parieto-occipital area and hippocampus on brain magnetic resonance imaging, and hypometabolism in the occipital lobe including the primary visual cortex on brain (18)F-fluorodeoxyglucose positron emission tomography.

Complete genome sequence of Thiomicrospira sp. strain V2501 isolated from 250 m below the ground level in Horonobe, Hokkaido, Japan.

A thiosulfate-oxidizing bacterium, Thiomicrospira sp. strain V2501, was isolated from groundwater collected in a terrestrial deep subsurface environment. This strain was capable of chemolithoautotrophic growth on CO2 and thiosulfate. Here, we report the 2,240,851 bp complete genome sequence of strain V2501.

Neuropsychological detection of the early stage of amnestic mild cognitive impairment without objective memory impairment.

AIM: We investigate the assessment method to detect the early stage of amnestic mild cognitive impairment (aMCI) using Wechsler Memory Scale - Revised (WMS-R) and Wechsler Adult Intelligence Scale - Third Edition (WAIS-III). METHODS: Three groups (normal group, aMCI group, and early aMCI group), controlled for age and years of education, underwent brain (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET), WAIS-III, WMS-R, and other tests. The early aMCI group does not fulfill the clinical diagnostic criteria of aMCI because patients do not have objective memory impairment, but their clinical symptoms and results of (18)F-FDG PET indicate that they should be included in the category of aMCI. RESULTS: The discrepancy of scores between Verbal IQ and General Memory had the highest accuracy in discriminating between normal and early aMCI groups. CONCLUSION: The cutoff point determined in this study is useful to detect an early stage of aMCI, which may be distinguished from aMCI using the current criteria.

Theoretical and experimental studies of circular dichroism of mono- and diazonia[6]helicenes.

Combined experimental and theoretical studies revealed the characteristic circular dichroism (CD) spectral profiles of mono- and diazonia[6]helicenes, which were distinctly different from those reported for parent [6]helicene and neutral (di)aza-analogues. Aza[6]helicenes and [6]helicene showed bisignate Cotton effects (CEs) at the (1)Ba and (1)Bb bands, along with a weak CE at the (1)Lb band, where the signs of the former bands are responsible for the helical chirality of the helicenes while the sign of the latter is susceptive to the various factors such as electronic and steric effects. Protonation to monoaza[6]helicenes produces azonia[6]helicenes, showing dramatic changes in the CE pattern from the two bisignate to a three positive, two negative CE extremum series of comparable magnitudes, while dual protonation to diaza[6]helicenes forming diazonia[6]helicenes led to only nominal changes (slightly different rotational strength and excitation energy) in the CE pattern. Such rather complicated and contrasting CE behaviors of mono- versus diazoniahelicenes are derived mostly from the electronic effects of (unsymmetrical) protonation because the structures of neutral, mono-, and dicationic species are essentially identical to each other. Compared with those of neutral (di)aza[6]helicenes, the experimental CD spectra of (di)azonia[6]helicenes were less satisfactorily reproduced by the theoretical calculations at the state-of-the-art RI-CC2/TZVPP//DFT-D2-B97-D/TZVP level, most probably due to the inadequate incorporation of the effects of solvation. Nevertheless, the bytheoretical predictions were reasonably accurate and highly valuable in assigning the observed CE and elucidating the origin of the elaborate CD spectral behaviors upon protonation through inspection of the molecular orbital configuration of each transition, encouraging the extended use of the present protocol for analyzing the CD spectral behavior of aza- and other heteroatom-incorporated helicenes upon protonation. The CD spectral behavior upon metal ligation will also be explained through further theoretical and experimental studies.

A role of Bradyrhizobium elkanii and closely related strains in the degradation of methoxychlor in soil and surface water environments.

We have reported that a leguminous bacterial strain, Bradyrhizobium sp. strain 17-4, isolated from river sediment, phylogenetically very close to Bradyrhizobium elkanii, degraded methoxychlor through O-demethylation and oxidative dechlorination. In the present investigation, we found that B. elkanii (USDA94), a standard species deposited in the Culture Collection, degraded methoxychlor. Furthermore, Bradyrhizobium sp. strain 4-1, also very close to B. elkanii, isolated from Japanese paddy field soil, degraded methoxychlor. These B. elkanii and closely related strains degraded methoxychlor through almost identical metabolic pathways, and cleaved the phenyl ring and mineralized. In contrast, another representative Bradyrhizobium species, B. japonicum (USDA110), did not degrade methoxychlor at all. Based on these findings, B. elkanii and closely related strains are likely to play an important role not only in providing the readily biodegradable substrates but also in completely degrading (mineralizing) methoxychlor by themselves in the soil and surface water environment.

Intelligence or years of education: which is better correlated with memory function in normal elderly Japanese subjects?

BACKGROUND: We compared differences in intelligence and memory function between normal elderly Japanese subjects with more years of education and those with fewer years of education. We also investigated clinical and neuropsychological factors that are strongly correlated with memory function. METHODS: There were 118 normal elderly subjects who underwent the Mini-Mental State Examination, Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III), and Wechsler Memory Scale Revised. Subjects with at least 13 years of education were categorized as the H group, and those with 12 years of education or less were categorized as the L group. RESULTS: Age and Mini-Mental State Examination scores were not significantly different between the two groups. On the WAIS-III, there were significant differences between the two groups in Verbal IQ and Full Scale IQ. On the Wechsler Memory Scale Revised, there were significant differences between the two groups in Visual Memory, General Memory, and Delayed Recall. Correlation coefficients between memory function and the other factors demonstrated significant but weak correlations between years of education and General Memory (R = 0.22) and between years of education and Delayed Recall (R = 0.20). Strong correlations were found between Verbal IQ and Verbal Memory (R = 0.45), between Verbal IQ and General Memory (R = 0.49), between Full Scale IQ and General Memory (R = 0.50) and between Full Scale IQ and Delayed Recall (R = 0.48). CONCLUSIONS: In normal elderly Japanese subjects, years of education weakly correlated with memory function while Verbal IQ, Full Scale IQ and Verbal Comprehension on WAIS-III had stronger correlations with memory function. Verbal IQ and Verbal Comprehension on WAIS-III were found to be insusceptible to the cognitive decline characteristic of Alzheimer's disease or amnestic mild cognitive impairment. Therefore, verbal intelligence, as measured by Verbal IQ and Verbal Comprehension, may be the most useful factor for inferring premorbid memory function in Alzheimer's disease or amnestic mild cognitive impairment patients.

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 [(123) I]-metaiodobenzylguanidine levels. Moreover, [(18) F]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.