CSF biomarkers for the differential diagnosis of Alzheimer's disease: A large-scale international multicenter study.

INTRODUCTION: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aß1-42), 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 Aß1-42 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 Aß1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.

[Biological markers for early diagnosis of Alzheimer's disease].

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.

The relationship between the diagnosis method of neuronal dysfunction (DIMENSION) and brain pathology in the early stages of Alzheimer's disease.

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 ß (Aß) 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/Aß42, and a positive correlation between Dσ and p-tau181/Aß42. CONCLUSION: Dα and Dσ were related to cerebral hypoperfusion and p-tau181/Aß42. 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.

Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.

OBJECTIVE: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aß42) to that of the major reaction product (Aß40). Although no PS1 mutations are present, altered Aß42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aß42 as amyloid. METHODS: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aß, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations. RESULTS: We previously reported that changes in the Aß42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. INTERPRETATION: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

Touch Panel-type Dementia Assessment Scale: a new computer-based rating scale for Alzheimer's disease.

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.

Specific feature of olfactory dysfunction with Alzheimer's disease inspected by the Odor Stick Identification Test.

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.

Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction.

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.

Development and evaluation of a computerized test battery for Alzheimer's disease screening in community-based settings.

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.

Effect of aromatherapy on patients with Alzheimer's disease.

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 aromatherapy 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 aromatherapy, 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 aromatherapy, 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 non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

Effect of monosodium L-glutamate (umami substance) on cognitive function in people with dementia.

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 < 0.05). At the follow-up assessment, the TDAS total scores in the MSG group showed significant improvement compared with those reported in the Control group (p < 0.05). Furthermore, there was a correlation of changes from pre-intervention to post-intervention between the TDAS and enjoyment of the meal (r = -0.299, p = 0.049). CONCLUSIONS: Our results suggest that continued ingestion of MSG has an effect on cognitive function. Furthermore, the patients with improved questionnaires about palatability survey showed greater improvement in cognitive function.

Sugar chains of cerebrospinal fluid transferrin as a new biological marker of Alzheimer's disease.

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.

N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease.

Gaucher disease (GD) is the most common form of sphingolipidosis and is caused by a defect of beta-glucosidase (beta-Glu). A carbohydrate mimic N-octyl-beta-valienamine (NOV) is an inhibitor of beta-Glu. When applied to cultured GD fibroblasts with F213I beta-Glu mutation, NOV increased the protein level of the mutant enzyme and up-regulated cellular enzyme activity. The maximum effect of NOV was observed in F213I homozygous cells in which NOV treatment at 30 microM for 4 days caused a approximately 6-fold increase in the enzyme activity, up to approximately 80% of the activity in control cells. NOV was not effective in cells with other beta-Glu mutations, N370S, L444P, 84CG and RecNciI. Immunofluorescence and cell fractionation showed localization of the F213I mutant enzyme in the lysosomes of NOV-treated cells. Consistent with this, NOV restored clearance of 14C-labeled glucosylceramide in F213I homozygous cells. F213I mutant beta-Glu rapidly lost its activity at neutral pH in vitro and this pH-dependent loss of activity was attenuated by NOV. These results suggest that NOV works as a chemical chaperone to accelerate transport and maturation of F213I mutant beta-Glu and may suggest a therapeutic value of this compound for GD.

Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients.

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.

Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects.

BACKGROUND: Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-ß precursor protein (APP). Successive cleavage of APP by ß- and γ-secretases generates the aggregatable amyloid-ß peptide (Aß), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aß 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 Aß40 correlated with levels of total p3-Alcα in all cohorts. CONCLUSIONS: We confirm that Aß40 is the most abundant Aß 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 Aß40, 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 Aß metabolism.

Usefulness of 18F-fluorodeoxyglucose positron emission tomography for diagnosis of asymptomatic giant cell arteritis in a patient with Alzheimer's disease.

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.