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Background/objectives This study assessed the effect of continuous ingestion of monosodium l-glutamate (MSG) on cognitive function and dietary score in dementia patients. Subjects/methods This was a single-blind, placebo-controlled trial involving 159 subjects with dementia residing in a hospital or nursing home. We assigned the subjects to a group that ingested MSG thrice daily (0.9 g/dose) (MSG group; n = 79) or a group that ingested NaCl thrice daily (0.26 g/dose) (Control group; n = 80). This study consisted of a 12-week intake period, followed by a 4-week follow-up period without the ingestion of MSG or NaCl. We performed physical examination, cognitive symptom tests (the Touch Panel-type Dementia Assessment Scale (TDAS) and Gottfries–Bråne–Steen Scale (GBSS)), palatability and behaviour questionnaires, and blood tests before and after the intervention and after the follow-up period. Results There were no significant differences in the TDAS and GBSS total scores between the groups before and after the intervention. However, regarding the TDAS sub-items, “the accuracy of the order of a process” did not deteriorate in the MSG group compared with that observed in the Control group (p

Objectives To examine whether the diagnosis method of neuronal dysfunction (DIMENSION), a new electroencephalogram (EEG) analysis method, reflected pathological changes in the early stages of Alzheimer's disease (AD), we conducted a comparative study of cerebrospinal fluid markers and single-photon emission computed tomography. Methods Subjects cincluded 32 patients in the early stages of AD with a Mini-Mental State Examination score ≥24 (14 men, 18 women; mean age, 77.3 ± 9.2 years). Cerebrospinal fluid samples were collected from AD patients, and cerebrospinal fluid levels of phosphorylated tau protein (p-tau) 181 and amyloid β (Aβ) 42 were measured with sandwich ELISA. EEG recordings were performed for 5 min with the subjects awake in a resting state with their eyes closed. Then, the mean value of the EEG alpha dipolarity (Dα) and the standard deviation of the EEG alpha dipolarity (Dσ) were calculated with DIMENSION. Single-photon emission computed tomography analyses were also performed for comparison with DIMENSION measures. Results Patients with parietal hypoperfusion had significantly increasing p-tau181, decreasing Dα, and increasing Dσ. In addition, there was a negative correlation between Dα and p-tau181, p-tau181/Aβ42, and a positive correlation between Dσ and p-tau181/Aβ42. Conclusion Dα and Dσ were related to cerebral hypoperfusion and p-tau181/Aβ42. DIMENSION was able to detect changes in the early-stage Alzheimer's brain, suggesting that it is possibility as a useful examination for early-stage AD with a difficult discrimination in clinical conditions. Moreover, EEG measurement is a quick and easy diagnostic test and is useful for repeated examinations.

Aim: Alzheimer's disease (AD) is one of the most significant diseases associated with ageing. As the disease progresses, symptoms including olfactory dysfunction often appear along with cognitive dysfunction. We examined olfactory and other indexes to investigate correlations between them and the validity of an olfactory test for screening for AD. Methods: To assess whether odorant identification will be a useful diagnostic tool, we investigated the olfactory ability of Alzheimer's disease patients (ADs) using the Odor Stick Identification Test for the Japanese. As a control, we compared ADs to aged people without AD or dementia. To investigate the relationship between olfactory loss and severity of AD, we used the Mini-Mental State Examination, Alzheimer's Disease Assessment Scale, biomarkers in spinal fluid and single-photon emission computed tomography as brain imaging. Results: In comparing the controls and ADs, we believe that there are significant differences, with ADs having particularly low activity with regard to olfactory function and some odorants. We showed that there was a definite correlation between cognitive and olfactory function. To confirm this, we sorted subjects by markers of severity scores for comparison. In all areas, the AD group had more serious olfactory dysfunction, including in the early stages of AD. Conclusion: This study suggests that olfactory tests such as the Odor Stick Identification Test for the Japanese can be useful for assessing severity of AD, including cognitive dysfunction. Further investigations will enable us to establish an olfactory assessment method for the screening or diagnosis of AD.

The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing/alternative processing of the amyloid precursor protein (APP) by γ-secretase (for review, see Gandy1 and Small and Gandy2). This misprocessing/alternative processing leads to a relative increase in the ratio of the level of a minor γ-secretase reaction product, amyloid-β42 (Aβ42), to that of the major reaction product, amyloid-β40 (Aβ40; Borchelt and colleagues3). Until now, little has been known about γ-secretase function in sporadic AD (SAD). We approached this issue by studying the metabolite peptides, p3-Alcα, that are derived from the processing by α-secretases and γ-secretases of the alcadeinα (Alcα), member of the alcadein (Alc) protein family. Alc proteins colocalize with APP in healthy mouse and SAD human brain,4 but they are entirely distinct from APP in their polypeptide sequence. In neurons, Alc proteins are complexed to APP via X11L adaptor molecules, raising the possibility that Alcs might be sorted and processed together with APP. Experimental evidence supports this reasoning. In the absence of X11L, both Alc and APP proteins are rapidly metabolized by proteolysis.5 Levels of the endogenous APP metabolite, Aβ, are elevated in the brains of X11L-deficient mice.6,7 Thus, taken together with similarities in their structure and cellular distribution, APP and Alc proteins would be predicted to undergo parallel metabolic fates (for APP and X11L, see Gandy1 and Suzuki and Nakaya8; for Alc, see Araki and colleagues,4,5,9). Alc proteins exist in mammalian neurons as 4 isoforms4: Alcα1, Alcα2, Alcβ, and Alcγ. Alcα, Alcβ, and Alcγ are encoded by independent genes, while Alcα1 and Alcα2 are splice variants derived from the Alcα gene. All 3 members of the Alc family (Alcα, Alcβ, and Alcγ) are cleaved by ADAM 10 and ADAM 17, which have been identified as the α-secretases for APP.10–13 Subsequent cleavage of the remaining Alc C-terminal fragments involves predominantly the presenilin 1-(PS1)-dependent γ-secretase, and this reaction liberates a short peptide that we have designated p3-Alcα into cell-conditioned media and into cerebrospinal fluid (CSF). The amino acid sequences of the various alternatively cleaved p3-Alcα peptides in human CSF are shown with those of APP-p3 and Aβ (Fig 1). The current study is based on the hypothesis that examination of AD-related processing of p3-Alcα might reveal evidence for γ-secretase dysfunction in SAD. In so doing, we seek to confirm and extend the report of Yanagida and colleagues,14 who described similar alternative processing of another γ-secretase substrate, APLP. Taken together with the data from Yanagida and colleagues,14 we suggest that multiple γ-secretase substrates are subjected to altered processing in SAD and that this potentially implicates an “acquired” γ-secretase dysfunction that might contribute the pathogenesis of SAD. Figure 1 Amino acid sequences and cleavage sites of p3-Alcα and Aβ in human CSF. The amino acid sequences of p3-Alcα (black-underline) along with the sequences of p3 (gray double-underline) and Aβ40 (black double-underline) of APP. ...

Background: The Alzheimer's Disease Assessment Scale (ADAS) was designed as a rating scale for the severity of dysfunction in the cognitive and non-cognitive behaviours that are characteristic of persons with Alzheimer's disease. Its subscale, the ADAS-cog, is a cognitive testing instrument most widely used to measure the impact of the disease. However, the ADAS-cog takes more than 45 min to administer and requires a qualified clinical psychologist as the rater. A more comprehensive rating battery is therefore required. In the present study, we developed a computerized test battery named the Touch Panel-type Dementia Assessment Scale (TDAS), which was intended to substitute for the ADAS-Cog, and was specifically designed to rate cognitive dysfunction quickly and without the need of a specialist rater. Methods: The hardware for the TDAS comprises a 14-inch touch panel display and computer devices built into one case. The TDAS runs on Windows OS and was bundled with a custom program made with reference to the ADAS-cog. Participants in the present study were 34 patients with Alzheimer's disease. Each participant was administered the ADAS-cog and the TDAS. The test scores for each patient were compared to determine whether the severity of cognitive dysfunction of the patients could be rated equally as well by both tests. Results: Pearson's correlation coefficient showed a significant correlation between the total scores (r= 0.69, P < 0.01) on the two scales for each patient. The Kendall coefficients of concordance obtained for the three corresponding pairs of tasks (word recognition, orientation, and naming object and fingers) showed the three TDAS tasks can rate symptoms of cognitive decline equally as well as the corresponding items on the ADAS-cog. Conclusions: The TDAS appears to be a sensitive and comprehensive assessment battery for rating the symptoms of Alzheimer's disease, and can be substituted for the ADAS-cog.

It is often difficult to diagnose disease in elderly patients, in particular those with dementia, who do not present with typical symptoms. This report describes our experience of an elderly patient (an 83-year-old woman) who presented with a chief complaint of memory loss, showed a marked inflammatory response, and was diagnosed with large-vessel giant cell arteritis (GCA) on the basis of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings. She had no symptoms typical of GCA including jaw claudication, visual field defect and heavy headed feeling. Corticosteroid therapy resulted in a trend toward improvement in the inflammatory response and then she first recognized that she might have experienced slight dull headache before treatment of GCA. This was probably because this patient had large-vessel GCA, which produces a few symptoms in the head and neck, and because she had Alzheimer's disease and could not accurately describe her symptoms. Our experience suggests the usefulness of FDG-PET for the diagnosis of GCA, particularly in elderly patients without typical symptoms. Geriatr Gerontol Int 2011; 11: 114–118.

Aim. To evaluate the capability of a computerized test battery for Alzheimer's disease screening which has been newly developed to provide a standardized and efficient method for widespread use in routine clinical and community-based settings. Methods. Participants were 72 individuals diagnosed with Alzheimer's disease and 102 healthy elderly individuals. Both groups were tested by the battery. Receiver operating characteristic analysis was used to examine the ability of the battery to differentiate between those with Alzheimer's disease and cognitively healthy elderly individuals. Results. On a group level, the Alzheimer's disease group performed worse than the control group on each of the 4 computerized test tasks. Receiver operating characteristic analysis yielded maximum sensitivity and specificity values of 96% and 86% for total scores, respectively. Conclusion. We believe the battery is very useful for routine clinical and community-based settings.

Introduction The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ 1–42 ), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. Methods A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. Results CSF Aβ 1–42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32–62) to 77% (for FTD, 95% CI = 62–90). Discussion CSF Aβ 1–42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.

In recent years, Alzheimer's disease (AD) has increased in incidence in Japan and elsewhere, and the marketing of donepezil hydrochloride (Aricept®) has allowed for the treatment of AD. These circumstances have encouraged the development of and research in markers for the early diagnosis of AD. Currently, the measurement of phosphorylated tau protein in the cerebrospinal fluid is considered to provide the most reliable and useful diagnostic marker for AD. For this purpose, a screening test using a touch panel computer can be recommended. The results of our study also suggest that the analysis of acetylcholine receptor α7 genetic polymorphism may be useful as a marker in the treatment with acetylcholine esterase inhibitors.

Background: Mild cognitive impairment (MCI) refers to the clinical condition between normal aging and Alzheimer's disease (AD) and has a high probability of developing into AD. Early detection of MCI is important because early detection and appropriate follow-up treatment can prevent the disease from progressing. Therefore, MCI is an important candidate for screening and possible intervention. Methods: We have developed a computerized screening test system to identify cognitive decline. This system consists of six tests (age and year-of-birth validity test, three-word memory test, time orientation test, first modified delayed-recall test, visual working memory test and second modified delayed-recall test). The scores obtained from three groups (MCI patients, AD patients and healthy control subjects) were analyzed to evaluate the sensitivity and specificity required for the screening of MCI. Results: The system was well accepted by the patients. All of the test procedures were completed within 5 min. Significant group differences in all test results were found. The system has sensitivity and specificity values of 82% and 87%, respectively, when used as a screen for MCI. Conclusion: The system is useful for the screening of cognitive disorders.

Niemann-Pick disease type C (NP-C) is an autosomal recessive lipid-storage disease that is characterized by progressive neurodegeneration and hepatosplenomegaly. Since identification of the NPC1 gene in 1997, a total of 120 disease-causing mutations have been reported. In this study, two novel mutations were identified, namely c.2508[-2509]A del (837Fs-838X) in exon 16 and T3194G (V1065G) in exon 21. To explore the impact of NPC1 mutations on transcription of this gene, we analyzed NPC1 mRNA levels in skin fibroblasts derived from NP-C patients. Fibroblasts from patients with missense mutations showed increased levels of NPC1 mRNA while fibroblasts from patients with a specific frameshift mutation showed mRNA levels similar to those of normal control subjects. These results suggest that NPC1 transcription levels are altered in cells with mutations in the NPC1 gene.

Dementia is a declined state of cognitive functions which impair daily and social life mainly caused by progressive neurodegenerative disease, such as Alzheimer's disease(AD). The present study showed that about 15% of patients in Japan aged over 65 have dementia. The important point regarding the diagnosis of dementia is to detect it as early as possible. It is critical for the diagnosis to measure the indicators in blood and cerebrospinal fluid (CSF). Blood tests are useful to eliminate other factors that lead to cognitive decline derived from physical causes. CSF markers are significant for monitoring the existence and progression of neuropathologies. We need to accumulate extensive knowledge of the features, types, pathologies, development, and progress of dementia in order to assess patients and/or measured values.

Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral lipid storage disorder biochemically characterized by a defect in intracellular transport of low-density lipoprotein (LDL)-derived cholesterol from the lysosome to other cellular sites. We have found substantial accumulation of GM2 ganglioside in NP-C fibroblasts. The intracellular distribution of GM2 ganglioside was similar to that of cholesterol detected by filipin staining, indicating that the accumulation of GM2 ganglioside is mainly lysosomal. The incorporation of N-acetyl-D-[3H]mannosamine into gangliosides was also increased in NP-C fibroblasts, especially into the GM2 and GM3 fractions. A culture condition which eliminates cholesterol accumulation does not eliminate GM2 accumulation. It is suggested that the accumulation of GM2 ganglioside together with the accumulation of cholesterol is a unique abnormality in NP-C fibroblasts and that the defect in NP-C may involve intracellular transport of both cholesterol and GM2 ganglioside.

To examine whether the diagnosis method of neuronal dysfunction (DIMENSION), a new electroencephalogram (EEG) analysis method, reflected pathological changes in the early stages of Alzheimer's disease (AD), we conducted a comparative study of cerebrospinal fluid markers and single-photon emission computed tomography.Subjects cincluded 32 patients in the early stages of AD with a Mini-Mental State Examination score ≥24 (14 men, 18 women; mean age, 77.3 ± 9.2 years). Cerebrospinal fluid samples were collected from AD patients, and cerebrospinal fluid levels of phosphorylated tau protein (p-tau) 181 and amyloid β (Aβ) 42 were measured with sandwich ELISA. EEG recordings were performed for 5 min with the subjects awake in a resting state with their eyes closed. Then, the mean value of the EEG alpha dipolarity (Dα) and the standard deviation of the EEG alpha dipolarity (Dσ) were calculated with DIMENSION. Single-photon emission computed tomography analyses were also performed for comparison with DIMENSION measures.Patients with parietal hypoperfusion had significantly increasing p-tau181, decreasing Dα, and increasing Dσ. In addition, there was a negative correlation between Dα and p-tau181, p-tau181/Aβ42, and a positive correlation between Dσ and p-tau181/Aβ42.Dα and Dσ were related to cerebral hypoperfusion and p-tau181/Aβ42. DIMENSION was able to detect changes in the early-stage Alzheimer's brain, suggesting that it is possibility as a useful examination for early-stage AD with a difficult discrimination in clinical conditions. Moreover, EEG measurement is a quick and easy diagnostic test and is useful for repeated examinations.

The Alzheimer's Disease Assessment Scale (ADAS) was designed as a rating scale for the severity of dysfunction in the cognitive and non-cognitive behaviours that are characteristic of persons with Alzheimer's disease. Its subscale, the ADAS-cog, is a cognitive testing instrument most widely used to measure the impact of the disease. However, the ADAS-cog takes more than 45 min to administer and requires a qualified clinical psychologist as the rater. A more comprehensive rating battery is therefore required. In the present study, we developed a computerized test battery named the Touch Panel-type Dementia Assessment Scale (TDAS), which was intended to substitute for the ADAS-Cog, and was specifically designed to rate cognitive dysfunction quickly and without the need of a specialist rater.The hardware for the TDAS comprises a 14-inch touch panel display and computer devices built into one case. The TDAS runs on Windows OS and was bundled with a custom program made with reference to the ADAS-cog. Participants in the present study were 34 patients with Alzheimer's disease. Each participant was administered the ADAS-cog and the TDAS. The test scores for each patient were compared to determine whether the severity of cognitive dysfunction of the patients could be rated equally as well by both tests.Pearson's correlation coefficient showed a significant correlation between the total scores (r= 0.69, P0.01) on the two scales for each patient. The Kendall coefficients of concordance obtained for the three corresponding pairs of tasks (word recognition, orientation, and naming object and fingers) showed the three TDAS tasks can rate symptoms of cognitive decline equally as well as the corresponding items on the ADAS-cog.The TDAS appears to be a sensitive and comprehensive assessment battery for rating the symptoms of Alzheimer's disease, and can be substituted for the ADAS-cog.

It is often difficult to diagnose disease in elderly patients, in particular those with dementia, who do not present with typical symptoms. This report describes our experience of an elderly patient (an 83-year-old woman) who presented with a chief complaint of memory loss, showed a marked inflammatory response, and was diagnosed with large-vessel giant cell arteritis (GCA) on the basis of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings. She had no symptoms typical of GCA including jaw claudication, visual field defect and heavy headed feeling. Corticosteroid therapy resulted in a trend toward improvement in the inflammatory response and then she first recognized that she might have experienced slight dull headache before treatment of GCA. This was probably because this patient had large-vessel GCA, which produces a few symptoms in the head and neck, and because she had Alzheimer's disease and could not accurately describe her symptoms. Our experience suggests the usefulness of FDG-PET for the diagnosis of GCA, particularly in elderly patients without typical symptoms.

A strong-base-induced intramolecular cycloaddition reaction of homophthalic anhydrides has been examined as a method for preparing nonlinear polycyclic peri-hydroxy aromatic compounds

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer’s disease (AD). Methods: After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherpay, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer’s disease (FAST), a revised version of Hasegawa’s Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherpay, and after the washout period. Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit’s score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests. Conclusions: In conclusion, we found aromatherapy an efficacious nonpharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.

A strong-base-induced intramolecular cycloaddition reaction of homophthalic anhydrides has been examined as a method for preparing nonlinear polycyclic peri-hydroxy aromatic compounds

Background/Aims: Alzheimer’s disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. Methods: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by lectin blotting using wheat germ agglutinin (WGA), and sugar chain analysis was performed by isoelectric focusing. Results: In Alzheimer’s CSF, several glycoproteins had lower WGA-binding activities, one of which was sufficiently sensitive and specific to distinguish AD from nondemented controls and other dementias. Further analysis identified this glycosylated protein as transferrin, and altered sugar chain composition of transferrin isoforms was observed despite normal protein levels in CSF. Conclusion: The decreased WGA-binding activity of transferrin in AD is probably due to altered glycosylation of transferrin molecules. Transferrin glycosylation is thus a potential biological marker for AD diagnosis, and changes in this glycosylation may play an important role in the pathophysiology of AD.

A 15-year-old boy was suffering from splenomegaly and a 10-year history of a neurologic disorder that included mental retardation, vertical supranuclear gaze palsy, dysarthria, ataxia, and dystonia. Bone marrow aspirates revealed foamy cells with storage materials which were positive with filipin staining. Cultured skin fibroblasts derived from the patient showed moderate loss of sphingomyelinase activity and the impairment of cholesterol esterification. The characteristic clinical presentations and typical histochemical findings of this patient met the diagnostic criteria of Niemann-Pick disease type C (NPC). In the fibroblasts from the patient, there was an accumulation of GM2 ganglioside around their cytoplasms. Increased levels of glycolipids. including GM2 ganglioside are reported in the cerebral cortex of NPC, but not in the fibroblasts. The fibroblasts derived from NPC may reflect the abnormal metabolism of glycolipids in the central nervous system of NPC.

Complementary and genomic DNAs isolated from the fibroblasts of 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and one Caucasian patient with Niemann-Pick disease type C were analyzed for mutations in the NPC1 gene. Fourteen novel mutations were found including small deletions and point mutations. A one-base deletion and a point mutation caused splicing errors. The mutations were not clustered in any particular region of the gene and were found both in and out of the transmembrane domains. Three patients were homozygous, five were compound heterozygous, and the remaining three were suspected of being compound hetrozygous with an unknown error in one of their NPC1 alleles. Of the 14 mutations, the G1553A substitution that caused a splicing error of exon 9 appeared to be relatively common in Japanese patients, because two patients were homozygous and one patient was compound heterozygous for this mutation.

Cultured fibroblasts from patients with Niemann-Pick disease type C (NP-C) are characterized by lysosomal accumulation of unesterified cholesterol and a defect in intracellular trafficking of cholesterol. We have found the accumulation of GM2 ganglioside in NP-C fibroblasts [Yano T, Taniguchi M, Akaboshi S, Vanier MT, Tai T, Sakuraba H, et al. Proc Japan Acad 1996;72B:214–219]. In this communication we show that several inhibitors known to inhibit intracellular cholesterol transport, progesterone, imipramine and KN-62, elicit accumulation of not only unesterified cholesterol but also GM2 ganglioside. This finding suggests that intracellular transport of cholesterol may be coupled with that of GM2 ganglioside. The accumulation of free cholesterol and GM2 ganglioside may be a clue for understanding the basic defect of NP-C. Recently NPC1 gene is found by the positional cloning. The mechanism of accumulating of GM2 ganglioside should be further investigated by studying of the functions of NPC1 gene.

Niemann–Pick disease type C (NP-C) is an autosomal recessive disorder characterized by the sequestration and trapping of endocytosed cholesterol in lysosomes. The NPC1 gene on chromosome 18 was recently identified but its physiological function remains unknown. We have studied the lipid compositions of cultured human NP-C fibroblasts and mouse SPM-3T3 cell line derived from the C57BL/KsJ NP-C model mouse, which belongs to the same complementation group. Fibroblasts derived from apparently normal age-matched individuals and a subline of SPM-3T3 cells which restores cholesterol metabolism by transfer of human chromosome 18 were used as controls. Levels of free cholesterol in whole cell homogenates increased about 1.5-fold in human NP-C fibroblasts and mouse SPM-3T3 cells, while in the plasma membrane, cholesterol content did not significantly change in NP-C fibroblasts but rather decreased in SPM-3T3 cells. The total phospholipid content did not significantly change; however, among phospholipid head groups, increases in sphingomyelin and decreases in other classes were observed in human NP-C fibroblasts and mouse SPM-3T3 cells. The ratios of saturated fatty acids to unsaturated fatty acids increased in both human and mouse cells. The increase was also confirmed in the plasma membrane fraction of SPM-3T3 cells. Membrane fluidity was examined using a 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescent probe. The DPH anisotropy values were markedly increased in NP-C fibroblasts and in SPM-3T3 cells. The results suggest that a NP-C mutation causes complex alterations in cellular lipid contents and biophysical properties of the membrane.

A strong base-induced intramolecular cycloaddition reaction homophthalic anhydride has been examined as a method for preparing polycyclic perihydroxy aromatic compounds.

A strong base-induced intramolecular cycloaddition reaction homophthalic anhydride has been examined as a method for preparing polycyclic perihydroxy aromatic compounds.

Background Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aβ and p3-Alcα can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcα in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). Results Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcα, we determined levels of total p3-Alcα in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Aβ40 correlated with levels of total p3-Alcα in all cohorts. Conclusions We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3-Alcα can serve as a either (1) a nonaggregatable surrogate marker for γ-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alcα and Aβ40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of γ-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Aβ metabolis