Analysis of patch testing with cocamidopropyl betaine and its impurities in patients with intractable scalp dermatitis in a single clinic in Japan.

BACKGROUND: The allergen responsible for cocamidopropyl betaine (CAPB) allergies has been debated. OBJECTIVES: To investigate the sensitizing agents of CAPB, the patch test positivity rates of impurities were examined in Japanese patients with CAPB-related allergic contact dermatitis. MATERIALS AND METHODS: Thirty patients with scalp dermatitis and positive patch tests for CAPB and/or lauramidopropyl betaine (LAPB) were enrolled in this study. They were patch tested with the detergents that they had been using at the time of their first visit and with the impurities dimethylaminopropylamine (DMAPA) and lauramidopropyl dimethylamine (LAPDMA). RESULTS: The positivity rate in patch tests of the 37 detergents that the patients had been using was 78.4% (29/37). The positivity rates of DMAPA 1% pet., 1% aq. and 0.2% aq. were 32.1% (9/28), 14.3% (4/28) and 13.3% (4/30), respectively, whereas those of LAPDMA 0.1% and 0.05% were 30.0% (9/30) and 16.7% (5/30), respectively. Among the 30 patients, 6 exhibited positive results for both DMAPA and LAPDMA, 3 showed positive results for DMAPA alone and 6 produced positive results for LAPDMA alone. CONCLUSION: Patch tests produced an overall positivity rate for DMAPA, LAPDMA or both of 50.0% (15/30) in patients with scalp dermatitis and positive patch test results for CAPB and/or LAPB.

[ANALYSIS OF PATCH TEST RESULTS USING COCAMIDOPROPYL BETAINE-RELATED SURFACTANTS].

BACKGROUND: A few previous studies have compared the patch test (PT) results obtained using different types of PT units. OBJECTIVES: This study aimed to compare PT results between the Patch Tester 'Torii' and Finn Chamber. METHODS: Thirty-four patients with intractable scalp dermatitis were enrolled in this study. PT were performed with three kinds of amphoteric surfactants, cocamidopropyl betaine (CAPB), high-concentration CAPB (h-CAPB), and lauramidopropyl betaine (LAPB), using both the Patch Tester 'Torii' and Finn Chamber, and the changes in the subjects' symptoms after they stopped using these surfactants were examined. RESULTS: Regarding the PT results for CAPB, h-CAPB, and LAPB, the results obtained with the Finn Chamber included a significantly lower frequency of irritant reactions (CAPB; p=0.003, h-CAPB; p=0.046, LAPB; p=0.002) than those obtained with the Patch Tester 'Torii'. However, there were no significant differences in the frequencies of positive reactions between the Patch Tester 'Torii' and Finn Chamber in each surfactant. The same tendency was seen in PT with LAPB (p=0.041) in 17 selected patients, who showed positive or doubtful reactions in PT performed with the surfactant-containing products they had used and whose symptoms 'markedly improved' or 'improved' after they stopped using these products. Among these surfactants, CAPB exhibited the highest positivity rate; however, the differences were not significant. CONCLUSION: In patients with intractable scalp dermatitis, PT of the abovementioned surfactants performed using the Finn Chamber were superior to those conducted using the Patch Tester 'Torii' because they resulted in fewer irritant reactions.

[ANALYSIS OF PATCH TEST RESULTS FOR INDIVIDUAL INGREDIENTS IN PATIENTS WITH ALLERGIC CONTACT DERMATITIS CAUSED BY 10% EFINACONAZOLE NAIL SOLUTION].

BACKGROUND: Ten percent efinaconazole nail solution (EFCZ solution) is a new topical triazole antifungal drug, and we sometimes encounter patients with allergic contact dermatitis (ACD) caused by EFCZ solution in our outpatient clinic. However, no previous reports have summarized the patch test (PT) results obtained for individual ingredients in several patients with EFCZ solution-induced ACD. OBJECTIVES: This study aimed to 1) confirm the causative agent of EFCZ solution-induced ACD based on PT of individual ingredients and 2) analyze the optimal concentration and vehicle for such PT on the basis of previous studies. PATIENTS AND METHODS: We clinically diagnosed eight patients with EFCZ solution-induced ACD from Sep. 2014 to Aug. 2021, and performed 48-hour closed PT using EFCZ solution and its ingredients. Readings were done on days (D) 2, 3, and 7 according to the International Contact Dermatitis Research Group criteria. RESULTS: Six of the 8 patients underwent PT with EFCZ solution, and all showed + to +++ reactions on D3. The results for the main component, EFCZ, were + to +++ on D3 in all patients. Two patients were patch tested with both 10% EFCZ in ethanol and 10% EFCZ in petrolatum, which produced similar reactions. One patient had an allergic reaction to ethanol. CONCLUSIONS: The causative agent of EFCZ solution-induced ACD was EFCZ in all patients. For PT, we recommend EFCZ solution as is, its 10-fold dilution and 1% and 0.1% EFCZ in petrolatum.

[A CASE OF ALLERGIC CONTACT DERMATITIS CAUSED BY DETERGENTS CONTAINING COCAMIDOPROPYL BETAINE IN WHICH AN IMPURITY WAS THE POSSIBLE CAUSATIVE AGENT].

Cocamidopropyl betaine (CAPB) is an amphoteric surfactant. It has several functions, including producing effervescence and washing effects, and thus, it is used in many cleansing products, such as shampoo and liquid body cleansers. Recently, it has become clear that some impurities that arise during the manufacturing process can have sensitizing effects. Herein, we report a case of allergic contact dermatitis caused by detergents containing CAPB, in which an impurity was determined to be the possible causative agent by patch testing and chemical analysis.A 64-year-old Japanese female developed a skin rash on the hairlines of her forehead and nuchal region one month before her first visit to our clinic. Later, the rashes, which were composed of desquamative erythema, expanded to her face, neck, upper back, and chest. Patch tests produced positive results for a shampoo and liquid body cleanser (1% aq.) that she had used as well as for CAPB (1% aq.); lauramidopropyl betaine (LAPB) (1% aq.); and lauramidopropyl dimethylamine (LAPDMA) (0.05% aq.), which is an impurity of CAPB. The rashes resolved completely after we instructed her to use products without CAPB and LAPB. When issuing such instructions, clinicians should have correct knowledge about surfactants, such as the differences between cosmetic ingredient names and quasi-drug ingredient names.

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver.

Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2α (HIF-2α), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, we examined whether liver-derived EPO improved anemia in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2α and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2α level from 0.27 to 1.53 fmol/mg and the EPO mRNA expression level by 1300-fold in the livers of healthy rats. After administration of TP0463518 at 20 mg/kg, the total EPO mRNA expression level in the whole liver was 22-fold that in the whole kidney. In bilaterally nephrectomized rats, TP0463518 raised the serum EPO concentration from 0 to 180 pg/ml at 20 mg/kg. Furthermore, repeated administration of TP0463518 at 10 mg/kg increased the reticulocyte count in 5/6 Nx rats on day 7 and raised the hemoglobin level on day 14. The present study revealed that TP0463518 specifically induced EPO production in the liver and improved anemia. The characteristic feature of TP0463518 would lead to not only a more detailed understanding of the PHD-HIF2α-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver; however, their effects on renal EPO production have been shown to vary depending on the experimental conditions. The authors found that 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518), a PHD 1/2/3 pan inhibitor, specifically induced EPO production in the liver and that the liver-derived EPO was pharmacologically effective. Investigation of the effects of TP0463518 may pave the way for the development of a new therapeutic alternative for renal anemia patients.

Novel Compound Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease Patients and Healthy Volunteers.

BACKGROUND: TP0463518 is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor developed to aid in the treatment of anemia associated with chronic kidney disease (CKD) and is expected to increase erythropoietin (EPO) derived from liver. Two phase I studies were conducted in healthy volunteers (HV) and CKD patients undergoing hemodialysis (i.e., HD patients) or those not undergoing dialysis (i.e., ND patients). METHODS: Pharmacokinetics, pharmacodynamics, and safety profiles of TP0463518 were assessed. Forty HV received single oral doses of TP0463518 at 3, 6, 11, 20, and 36 mg or placebo. Twenty ND patients received single doses of TP0463518 at 1, 6, and 11 mg and 9 HD patients received TP0463518 at 1 and 11 mg doses. To identify the source organ of EPO, glycosylation patterns were determined using percentage migrated isoform (PMI) values. RESULTS: Declining renal function slowed elimination of TP0463518 and increased the mean AUC0-∞. ∆Emax of serum EPO in 11-mg groups of HV, ND patients, and HD patients were 24.37 ± 11.37, 201.57 ± 130.34, and 1,324.76 ± 1,189.24 mIU/mL respectively. A strong correlation was -observed between logarithm conversions of ∆Emax and AUC0-∞ with correlation coefficients of 0.945. PMI values of blood after TP0463518 administration were elevated to similar or higher levels in comparison with those of umbilical cord blood, which mainly contains liver-derived EPO. CONCLUSIONS: TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions.

Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal anemia.

Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.

Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane derivatives as GPR119 agonists.

The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R2) and the left aryl group (R3) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats.

Novel 3H-[1,2,3]triazolo[4,5-c]pyridine derivatives as GPR119 agonists: Synthesis and structure-activity/solubility relationships.

We previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound's significantly poor aqueous solubility (0.71µM at pH6.8). In this article, we describe the further optimization of compound 4b focusing on the improvement of its aqueous solubility. Optimization of the central spacer, left-hand aryl group and right-hand piperidine N-capping group led to the identification of a potent GPR119 agonist, 3H-[1,2,3]triazolo[4,5-c]pyridine derivative 32o, with improved solubility (15.9µM at pH6.8).

Design and synthesis of 1H-pyrazolo[3,4-c]pyridine derivatives as a novel structural class of potent GPR119 agonists.

Design and synthesis of a novel class of 1H-pyrazolo[3,4-c]pyridine GPR119 receptor agonists are described. Lead compound 4 was identified through the ligand-based drug design approach. Modification of the left-hand aryl group (R(1)) and right-hand piperidine N-capping group (R(2)) led to the identification of compound 24 as a single-digit nanomolar GPR119 agonist.

Serum zinc levels in patients with phlegmons as a marker of the severity of infection and the potential of zinc supplementation to reduce the risk of recurrence.

We analyzed the serum zinc levels of 37 patients with 40 phlegmon lesions. The mean serum zinc level was 52.1 ± 16.4 µg/dL. The serum zinc level was negatively correlated with the C-reactive protein (CRP) level (r = -0.66) and white blood cell (WBC) count (r = -0.56). It was also positively correlated with the serum levels of albumin, hemoglobin, and hematocrit (r = 0.57, 0.50, and 0.50, respectively). Patients with serum zinc levels of <60 µg/dL had higher CRP levels and WBC counts (p < 0.005 and p < 0.05, respectively) and lower albumin, hemoglobin, and hematocrit levels (p < 0.001, p < 0.01, and p < 0.01, respectively), and were more likely to be hospitalized (p < 0.05) than those with serum zinc levels of ≥60 µg/dL. Patients with low serum zinc levels were given zinc tablets. Three of the seven patients who developed recurrent phlegmons did not develop any further lesions after taking zinc tablets for >10 months. Of the remaining patients, one only developed a minimal lesion, and another two experienced recurrence twice but did not have any further lesions for 10 and 15 months, respectively. These findings indicate that in patients with phlegmons the serum zinc level is a suitable marker of the severity of infection, and zinc supplementation reduces the risk of further recurrence in patients whose lesions relapse.

Role of Interleukin-6 in the Antigen-Specific Mucosal Immunoglobulin A Responses Induced by CpG Oligodeoxynucleotide-Loaded Cationic Liposomes.

An advantage of mucosal vaccines over conventional parenteral vaccines is that they can induce protective immune responses not only at mucosal surfaces but also in systemic compartments. Despite this advantage, few live attenuated or inactivated mucosal vaccines have been developed and applied clinically. We recently showed that the intranasal immunization of ovalbumin (OVA) with class B synthetic oligodeoxynucleotides (ODNs) containing immunostimulatory CpG motif (CpG ODN)-loaded cationic liposomes synergistically exerted both antigen-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) responses in mice. However, the mechanism underlying the mucosal adjuvant activity of CpG ODN-loaded liposomes remains unknown. In the present study, we showed that the intranasal administration of CpG ODN-loaded cationic liposomes elicited interleukin (IL)-6 release in nasal tissues. Additionally, pre-treatment with an anti-IL-6 receptor (IL-6R) antibody attenuated antigen-specific nasal IgA production but not serum IgG responses. Furthermore, the intranasal administration of OVA and CpG ODN-loaded cationic liposomes increased the number of IgA+/CD138+ plasma cells and IgA+/B220+ B cells in the nasal passages. This increase was markedly suppressed by pre-treatment with anti-IL-6R blocking antibody. In conclusion, IL-6 released by CpG ODN-loaded cationic liposomes at the site of administration may play a role in the induction of antigen-specific IgA responses by promoting differentiation into IgA+ plasma cells for IgA secretion from B cells.

TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation.

Hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor stabilizes hypoxia inducible factor alpha, which increases erythropoietin (EPO) expression via the hypoxia response element. Therefore, PHDs inhibitors have been developed as novel therapeutic agents for anemia. Here, we characterize the in vitro and in vivo pharmacological profiles of TP0463518, 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid, a novel potent PHDs inhibitor. TP0463518 competitively inhibited human PHD2 with a Ki value of 5.3 nM. TP0463518 also inhibited human PHD1/3 with IC50 values of 18 and 63 nM as well as monkey PHD2 with an IC50 value of 22 nM. In normal mice and rats, TP0463518 significantly increased the serum EPO levels at doses of 5 and 20 mg/kg, respectively. The correlation factors for serum EPO and the serum TP0463518 levels were 0.95 in mice and 0.92 in rats. TP0463518 also increased the serum EPO level in 5/6 nephrectomized chronic kidney disease model rats at a dose of 10 mg/kg, with a correlation factor for serum EPO and the serum TP0463518 levels of 0.82. Finally, the effect of TP0463518 in monkeys was investigated. TP0463518 was promptly removed with a half-life of 5.2 h and increased the area under the curve (AUC) of EPO at a dose of 5 mg/kg. The EPO and TP0463518 levels were also correlated. These results suggest that TP0463518 induces endogenous EPO with a strong pharmacokinetic-pharmacodynamic correlation and may contribute to desirable hemoglobin control in patients with renal anemia.

Case of cholinergic urticaria accompanied by anaphylaxis.

Cholinergic urticaria occasionally occurs in combination with anaphylactic symptoms. However, this has not been widely reported. Herein, we report the case of a 14-year-old Japanese male who was diagnosed with cholinergic urticaria accompanied by anaphylaxis. The patient, who was suffering from atopic dermatitis and bronchial asthma, had developed wheals after exercising or bathing, which would have increased his core body temperature, since summer 2014. He experienced two episodes of severe systemic symptoms and wheal development when he took a bath after eating in December 2014 and the following January. His symptoms included wheezing, numbness of the lips, respiratory distress, blindness and fainting. Laboratory tests revealed the following results: serum IgE level, 7060 IU/mL; titers of specific immunoglobulin E antibodies against Malassezia and MGL_1304, 31.70 UA/mL and 112.5 ng/mL, respectively. A histamine release test against human sweat revealed a class 4 response. Skin prick and intradermal tests against autologous sweat produced immediate-type positive reactions. According to these findings, we diagnosed him with the sweat-hypersensitivity type of cholinergic urticaria accompanied by anaphylaxis. He was successfully treated with lafutidine, a histamine H2 receptor antagonist, in combination with fexofenadine. It is important for dermatologists to be aware that cholinergic urticaria can progress to anaphylaxis.

Intranasal Immunization with DOTAP Cationic Liposomes Combined with DC-Cholesterol Induces Potent Antigen-Specific Mucosal and Systemic Immune Responses in Mice.

Despite the progress made by modern medicine, infectious diseases remain one of the most important threats to human health. Vaccination against pathogens is one of the primary methods used to prevent and treat infectious diseases that cause illness and death. Vaccines administered by the mucosal route are potentially a promising strategy to combat infectious diseases since mucosal surfaces are a major route of entry for most pathogens. However, this route of vaccination is not widely used in the clinic due to the lack of a safe and effective mucosal adjuvant. Therefore, the development of safe and effective mucosal adjuvants is key to preventing infectious diseases by enabling the use of mucosal vaccines in the clinic. In this study, we show that intranasal administration of a cationic liposome composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl] (DC-chol) (DOTAP/DC-chol liposome) has a potent mucosal adjuvant effect in mice. Intranasal vaccination with ovalbumin (OVA) in combination with DOTAP/DC-chol liposomes induced the production of OVA-specific IgA in nasal tissues and increased serum IgG1 levels, suggesting that the cationic DOTAP/DC-chol liposome leads to the induction of a Th2 immune response. Additionally, nasal-associated lymphoid tissue and splenocytes from mice treated with OVA plus DOTAP/DC-chol liposome showed high levels of IL-4 expression. DOTAP/DC-chol liposomes also enhanced OVA uptake by CD11c+ dendritic cells in nasal-associated lymphoid tissue. These data demonstrate that DOTAP/DC-chol liposomes elicit immune responses via an antigen-specific Th2 reaction. These results suggest that cationic liposomes merit further development as a mucosal adjuvant for vaccination against infectious diseases.

Immunohistochemical study of synphilin-1 in brains of patients with dementia with Lewy bodies - synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.

Dementia with Lewy bodies brains were immunohistochemically investigated using anti-synphilin-1 antibodies. The alpha-synuclein-positive brainstem type and well-defined cortical type Lewy bodies (LB) were positive for synphilin-1, while ill-defined LB and LB-related neurites were negative, suggesting that synphilin-1 does not directly associate with alpha-synuclein. Synphilin-1-positive LB were double-positive for phosphorylated neurofilament. In addition, tau-positive neurofibrillary tangles (NFT) were positive for synphilin-1, while neuropil threads were negative. Immunoelectron microscopically, synphilin-1 was located on filamentous components in cortical type LB and on paired helical filaments in NFT. It is likely that synphilin-1 accumulates in the cell body according to the axonal transport blockage, and associates with abnormal cytoskeltons during the formation of LB or NFT, suggesting that synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.

Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains.

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: comparison with late-onset Alzheimer's disease brains.

We quantitatively investigated the formation process of neurofibrillary tangles (NFT) in the hippocampus of 32 brains from non-demented elderly persons using tau-immunohistochemistry, compared with 13 brains from patients with late-onset Alzheimer's disease (AD). The 32 non-demented elderly brains were classified into 16 brains in group I and 16 brains in group II mainly based on the distribution of tau-positive neurons in the hippocampus. Tau-positive neurons were found predominantly in the CA2 in group I, while they were found predominantly in the subiculum-pre-CA1 in group II. Most late-onset AD brains showed a distribution of tau-positive neurons similar to that in group II. In addition, the distribution pattern of tau-positive neurons in the hippocampus was closely related to degeneration of the perforant pathway with the accumulation of tau. These findings suggest that NFT occur first in the CA2 and extend to the subiculum-pre-CA1 in group I, while they occur first in the subiculum-pre-CA1 and extend to the CA2 later in group II, and that the NFT occurring in the subiculum-pre-CA1 are mainly related to degeneration of the perforating route and in the CA2 are related to the degeneration of the non-perforating route.

Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer's disease and limbic NFT dementia.

Brains of non-demented elderly people were divided into two groups according to the presence or absence of senile plaques (SP(+) and SP(-)). The regional number of NFT in each group were then quantitatively investigated and compared with that in the late-onset Alzheimer's disease (AD) group and the limbic NFT dementia (LNTD) group. NFT were divided into type 1, type 2 and type 3 according to the developmental stage. In addition, polymorphism of the apolipoprotein E (Apo E) gene was analyzed in all groups. The most frequent regions of NFT common to all groups were the transentorhinal cortex, the entorhinal cortex, the subiculum and cornu ammonis (CA)1 of the hippocampus. In the SP(+) group the proportion of type 3 was high in the transentorhinal cortex and entorhinal cortex, while type 1 or 2 were high in the subiculum and CA1, suggesting that NFT formation progresses from the parahippocampal cortex to the hippocampus. In the SP(-) group the proportion of type 3 was higher in the subiculum and CA1 than in the transentorhinal cortex and entorhinal cortex, suggesting that NFT formation is accelerated in the hippocampus. The late-onset AD group and LNTD group showed the patterns of NFT formation similar to those of the SP(+) group and SP(-) group, respectively. The frequency of the epsilon4 allele of the Apo E gene was significantly higher in the late-onset AD group and SP(+) group than in the LNTD group and SP(-) group, respectively. From these findings it is suggested that persons in the SP(+) group are likely to remain non-demented elderly persons or become a developmental matrix of late-onset AD with a risk factor of the epsilon4 allele, while those in the SP(-) group are likely to remain non-demented elderly persons or pass into LNTD without a risk factor of the epsilon4 allele.