An aspergillotic aneurysm of the internal carotid artery following allogeneic bone marrow transplantation: successful management with catheter coil embolization and long-term antifungal agents.

We report a case of a mycotic aneurysm of the internal carotid artery and cerebral hemorrhagic infarction resulting from Aspergillus middle ear infection in a patient with severe aplastic anemia who received unrelated bone marrow transplantation. Although a mycotic aneurysm is a rare complication, and most often fatal, the patient was successfully treated with catheter coil embolization of the internal carotid artery and long-term systemic antifungal therapy. This case emphasizes the need for the rapid diagnosis of potential fungal involvement of the vascular system and suggests the necessity for aggressive treatment, such as with the modality illustrated in this case.

Choledochal cyst associated with duodenal atresia: case report and review of the literature.

We report a rare case of choledochal cyst (CC) associated with congenital duodenal atresia (DA) and annular pancreas (AP). A girl was born at 37 weeks of gestation weighing 2,974 g with a prenatal diagnosis of DA. She underwent a duodenoduodenostomy for type III DA with an AP 1 day after birth. At 4 years of age, she was admitted for evaluation of cholangitis and pancreatitis. Radiological studies demonstrated a fusiform-type CC with pancreaticobiliary maljunction (PBMJ). Excision of the CC and hepaticojejunostomy were performed. The patient was discharged without complications. Despite the fact that CC, DA, and AP are embryologically closely related entities, to the best of our knowledge, only eight such cases have been documented. We must be aware of the possible combination of CC in the follow-up of the patients with DA associated with AP.

The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system.

Non-A beta component of Alzheimer's disease amyloid (NAC) is the second component in the amyloid from brain tissue of patients affected with Alzheimer's disease. Its precursor protein (NACP) was shown to be a brain-specific protein. In rat brain, NACP was more abundant in the neocortex, hippocampus, olfactory bulb, striatum, thalamus, and cerebellum and less abundant in the brain stem. Confocal laser microscopy analysis revealed that anti-NACP immunostaining was colocalized with synaptophysin-immunoreactive presynaptic terminals. Ultrastructural analysis showed that NACP immunoreactivity was associated with synaptic vesicles. NACP sequence showed 95% identity with that of rat synuclein 1, a synaptic/nuclear protein previously identified in rat brain, and good homology with Torpedo synuclein from the electric organ synapse and bovine phosphoneuroprotein 14 (PNP-14), a brain-specific protein present in synapses. Therefore, NACP is a synaptic protein, suggesting that synaptic aberration observed in senile plaques might be involved in amyloidogenesis in Alzheimer's disease.

Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors.

The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs) for allogeneic transplantation still need to be clarified, particularly in children. We compared the kinetics, efficacy, and safety of PBSC mobilization by granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years) and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures. Serum trough levels of G-CSF determined by ELISA were significantly lower in the 16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05). Although the WBC counts on days 4 and 5 were significantly higher in adults than in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+ cells/unit of blood were identical. The number of blood CD34+ cells collected per unit of blood processed was identical in both donor populations. We propose that PBSCs could be effectively mobilized and collected in small children so that they could be donors for adult patients.

Frequent aberration of FHIT gene expression in acute leukemias.

We analyzed the mRNA expression of the FHIT gene by reverse transcription-PCR (RT-PCR) in 54 cases of acute lymphoblastic leukemia (ALL; 11 cases of T-cell ALL [T-ALL] and 43 cases of non-T-ALL) and 40 cases of acute myeloid leukemia (AML). In 46% of the ALL cases and 55% of the AML cases, FHIT expression was absent or markedly decreased. Only abnormal short bands were detected in 30% of the ALL cases and 5% of the AML cases. Eighteen of 19 abnormal transcripts had the same fusion of exons 2-7, and all lacked the starting codon in exon 5. No obvious normal-sized PCR products were detected in cases exhibiting abnormal transcripts. These findings suggest that the expression of functional FHIT protein was lost in the majority of ALL (76%) and AML (60%) cases. Differential quantitative PCR of exons 3-9 of the FHIT gene and RT-PCR of the PTPRG gene, which is centromeric to the FHIT gene, showed the presence of the target sequences. Fluorescence in situ hybridization analysis using probes covering exons 5 and 8 revealed no difference in the signal patterns between leukemia and normal cells, showing one or two signal doublets in more than 90% of nuclei, and indicated that gross segments of the FHIT gene were not homozygously deleted in these cases. A small number of transcripts with an aberrant fusion between exons 2 and 7 were detected by RT-PCR in the bone marrow cells from four healthy individuals. Granulocytes, lymphocytes, and monocytes in the bone marrow cells of a healthy individual contained transcripts with the same fusion. This unique fusion of exons 2 and 7 might be preferentially seen in either neoplastic or normal hematopoietic cells, regardless of their lineage. The finding that FHIT expression was abolished in the majority of leukemia cases might support the hypothesis that the FHIT gene acts as a tumor suppressor, at least in leukemia.

Properties of NACP/alpha-synuclein and its role in Alzheimer's disease.

The precursor of the non-amyloid beta/A4 protein (non-Abeta) component of Alzheimer's disease amyloid (NACP)/alpha-synuclein is the human homologue of alpha-synuclein, a member of a protein family which includes alpha-, beta- and gamma-synuclein. This protein is thought to be involved in neuronal plasticity because of its unique expression, mainly in the telencephalon during maturation. Consequently, disarrangement of NACP/alpha-synuclein might disrupt synaptic activity, resulting in memory disturbance. Previous studies have shown that damage to synaptic terminals is closely associated with global cognitive impairment and is an early event in the pathogenesis of Alzheimer's disease. Although the relationship between synaptic damage and amyloidogenesis is not clear, some proteins at the synaptic site have been implicated in both neuronal alteration and amyloid formation. Indeed, abnormal accumulation of both NACP/alpha-synuclein and Abeta precursor protein occurs at synapses of Alzheimer's patients. Other evidence suggests that NACP/alpha-synuclein is a component of the Lewy bodies found in patients with Parkinson's disease or dementia with Lewy bodies, and that a point mutation in this protein may be the cause of familial Parkinson's disease. Consequently, abnormal transport, metabolism or function of NACP/alpha-synuclein appears to impair synaptic function, which induces, at least in part, neuronal degeneration in several neurodegenerative diseases.

Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan.

We analyzed tandem duplication in the juxtamembrane (JM) domain of the FLT3 (FMS-like tyrosine kinase 3/FLK2, CD135) gene in 94 children with acute myeloid leukemia (AML) and evaluated its correlation with clinical features. Longer polymerase chain reaction (PCR) products were observed in five patients; 1/3 of M0, 119 of M1, 1/39 of M2, 1/9 of M3 and 1/12 of M5. The sequence analyses of abnormal PCR products showed that all the abnormal products were derived from tandem duplications involving the JM domain and that all the lengthened sequences were in-frame as we previously reported. Statistical analyses revealed a significantly lower incidence of the tandem duplication in childhood AML patients than in adult patients (P < 0.05), and significantly shorter disease-free survival in patients with mutant FLT3 than in patients with wild-type FLT3 (P < 0.05). Our results suggest that the tandem duplication in the JM domain of the FLT3 gene is not a frequent phenomenon but might be a factor of poor prognosis in childhood patients with AML.

Effects of rhG-CSF (filgrastim) on the recovery of hematopoiesis after high-dose chemotherapy and autologous peripheral blood stem cell transplantation in children: a report from the Children's Cancer and Leukemia Study Group of Japan.

In a nonrandomized study, hematopoietic recovery kinetics were evaluated in 98 consecutive patients who underwent high-dose chemotherapy without total body irradiation (TBI) and autologous peripheral blood stem cell transplantation (PBSCT). Fifty-three patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) therapy after PBSCT, and the data were compared by actuarial analysis to those of 45 historic controls. The number of days required to achieve a white blood cell count (WBC) of 1 x 10(9)/L, an absolute granulocyte count (AGC) of 5 x 10(8)/L, and a platelet count (PLT) of 5 x 10(10)/L were, respectively, 12.8 +/- 6.4 (mean +/- standard deviation [SD]), 13.4 +/- 6.4, and 49.2 +/- 78.2 in treated patients vs. 12.8 +/- 4.6, 14.4 +/- 10.3, and 31.4 +/- 38.8 days in historic controls, with no significant differences. There was no significant difference between the average number of days with fever in the treated group (6.0 +/- 6.6) and that in the control group (4.0 +/- 2.8). All febrile episodes responded promptly and successfully to parenteral antibiotic therapy. Thus, the data may suggest the possibility that therapy with filgrastim has only a limited ability to enhance hematopoietic recovery after PBSCT. To confirm this notion, we initiated a prospective randomized trial by recruiting a larger number of patients.

Reduced sensitivity of inducible nitric oxide synthase-deficient mice to chronic colitis.

BACKGROUND: Overproduction of nitric oxide by the inducible form of nitric oxide synthase (iNOS) has been implicated in colitis. Different authors have postulated both toxic and protective effects of nitric oxide (NO) in the pathophysiology of active inflammation. The objective of this study was to examine the role of iNOS in experimental chronic colitis using iNOS-deficient mice. METHODS: For induction of colitis, mice received three cycles of 2% of dextran sodium sulfate (DSS) (M.W. 40,000) treatment in drinking water. The degree of colonic inflammation, leukocyte infiltration, and the expression of cell adhesion molecules were determined. INOS expression and nitrotyrosine were also determined by immunohistochemistry. RESULTS: After DSS treatment, a moderate colitis with marked cell infiltration was observed. Intense expression of iNOS was observed on infiltrating cells as well as on the colonic mucosal epithelium in these animals. In the iNOS-deficient mice, tissue damage was significantly diminished. No iNOS or nitrotyrosine staining was found in iNOS-deficient mice. The number of infiltrating cells and the expression of mucosal adressin cell adhesion molecule-1 were significantly attenuated in the DSS-treated colon of iNOS-deficient mice. CONCLUSION: Induction of iNOS seems to act as a critical toxic effector molecule in the pathogenesis of chronic colonic inflammation.

Neuroprotective effect of YM-39558 in focal cerebral ischemia in cats.

We studied the effect of YM-39558, orotic acid ethylester, in a focal cerebral ischemia model in anesthetized cats. YM-39558 has good permeability across the blood brain barrier, and in the brain is hydrolyzed to orotic acid, the main active substance. Cats were subjected to permanent occlusion of the middle cerebral artery (MCA) for 6 h, then killed and examined histologically. Treatment with YM-39558 (intravenous infusion of 11.8 mg (10 mg as orotic acid)/6 ml per kg per h) starting 15 min after MCA occlusion markedly reduced the volume of ischemic damage (from 2450 +/- 82 mm3 of the cerebral hemisphere in the saline-treated cats to 1644 +/- 123 mm3 in the YM-39558-treated cats, P < 0.01). In contrast, YM-39558 (2.26 and 1.18 mg/0.8 ml per kg per h) showed no significant protective effect on ischemic damage. No significant differences were observed between saline- and YM-39558-treated cats concerning physiological variables including brain temperature. This evidence for the neuroprotective efficacy of YM-39558 in gyrencephalic species suggests its therapeutic potential in the treatment of stroke in humans.

Effects of vasopressin and catecholamines on the maintenance of circulatory stability in brain-dead patients.

The effectiveness and reliability of long-term control of circulatory stability in brain-dead patients by combined administration of vasopressin and catecholamine was examined in detail. Twenty-five patients were divided into three groups according to the dose of vasopressin. The first group (n = 10) received no vasopressin, the second group (n = 2) an antidiuretic dose (0.1-0.4 U/hr), and the third group (n = 13) a pressor dose (1-2 U/hr), respectively. Patients given no vasopressin or an antidiuretic dose demonstrated circulatory deterioration and cardiac arrest within a short time after brain death, despite administration of a large dose of epinephrine. All patients with a pressor dose of vasopressin, however, demonstrated stable circulation as long as vasopressin and epinephrine were administered. Five patients in whom stable circulation was maintained by this technique were randomly chosen from the third group and studied under the following four conditions: (1) neither vasopressin nor epinephrine; (2) vasopressin only; (3) epinephrine only; and (4) both vasopressin and epinephrine. Compared with the controls (neither vasopressin nor epinephrine), vasopressin only increased the total peripheral resistance index, whereas epinephrine alone increased the cardiac index. Combined administration, however, raised the mean arterial blood pressure significantly by markedly increasing the total peripheral resistance index and cardiac index. Finally, in four brain-dead patients also randomly chosen from the third group, epinephrine, norepinephrine, and dopamine were compared in their circulatory effects with a pressor dose of vasopressin. Epinephrine increased both the total peripheral resistance index and cardiac index, whereas norepinephrine increased the total peripheral resistance index, compared with the baseline (no catecholamine). The required dose of norepinephrine, however, was four times that of epinephrine. The major effect of dopamine was to increase the cardiac index. We conclude that a pressor dose of vasopressin plays a central role in circulatory stabilization of brain-dead patients, and that long-term maintenance of stable circulation for a desired length of time is possible by the combined use of vasopressin and a catecholamine. Individually, catecholamines exhibit characteristic differences. Epinephrine has significant effects on both peripheral vessels and the heart, whereas norepinephrine keeps the circulation stable by increasing the total peripheral resistance index, with a much larger dose than epinephrine. Dopamine acts primarily on the heart.

beta-amyloid deposits in transgenic mice expressing human beta-amyloid precursor protein have the same characteristics as those in Alzheimer's disease.

A transgenic mouse expressing the human beta-amyloid precursor protein with the "Swedish" mutation, Tg2576, was used to investigate the mechanism of amyloid-beta peptide (Abeta) deposition. We characterized Abeta deposits in the cerebral cortex biochemically and pathologically. A surface-enhanced laser desorption/ionization affinity mass spectrometric study using the 6E10 monoclonal antibody demonstrated that the major species of Abeta in a formic acid-extracted fraction of the cortex were Abeta(1-38), Abeta(1-40) and Abeta(1-42). Immunohistochemistry using antibodies to the carboxy-terminal epitopes of Abeta(1-40) and Abeta(1-42), as well as 6E10, showed that plaques containing Abeta(1-42) were more numerous than those containing Abeta(1-40) throughout the cortex. Laser confocal analysis of the immunoreactivities in the plaques demonstrated that Abeta(1-40) was preferentially located in the central part of the Abeta(1-42) positive plaques. Enzyme-linked immunosorbent assay measurements of Abeta(1-40) and Abeta(1-42) showed that Abeta(1-40) was several-fold more abundant than Abeta(1-42). From these data we suggest that Abeta(1-42) deposition may precede Abeta(1-40) deposition, while Abeta(1-40) begins to deposit in the central part of the plaques and accumulates there. Furthermore, localization of Abeta(1-40) corresponded almost exactly to congophilic structures, which were associated with aberrant swollen synapses detected with antibodies to synaptophysin and alpha-synuclein. Thus, Abeta deposits in Tg2576 mice have similar characteristics to those in Alzheimer's disease.

Role of inducible nitric oxide synthase in dextran sulphate sodium-induced colitis.

BACKGROUND: Different authors have postulated both toxic and protective effects for nitric oxide (NO) in the pathophysiology of active inflammation. AIM: To examine the role of NO, especially that produced by the inducible form of nitric oxide synthase (iNOS), by investigating the effects of NOS inhibitors and NO donors on inflammation in experimental acute colitis. METHODS: Acute colitis was induced in rats by dextran sulphate sodium (DSS). White blood cell counts and levels of thiobarbituric acid reactants in the portal blood were determined, as were histological changes in the colonic mucosa. We then evaluated the effects of N(G)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and an NO donor on DSS-induced changes in these inflammatory parameters. RESULTS AND CONCLUSIONS: Inhibition of NO production by either L-NAME or AG worsened DSS-induced inflammation, suggesting a protective role for NO in acute colitis. On the other hand, a NO donor also exaggerated DSS-induced inflammatory parameters, suggesting that acute colitis may be aggravated by either too much or too little NO. These results suggest that medical treatment of ulcerative colitis must aim for maintenance of appropriate NO levels in the intestinal mucosa.

Peripheral blood stem cell mobilization with granulocyte colony-stimulating factor and a harvesting procedure in pediatric donors.

The safety of injecting healthy donors with granulocyte colony-stimulating factor (G-CSF) has not been established. To evaluate PBSC mobilization and harvesting efficacy in the pediatric population, we compared it with those in adult donors. In this study, we conclude that PBSC mobilization and harvesting protocol in normal pediatric donors can be performed safely and effectively. Considering the lower frequency of side-effects and WBC counts, and G-CSF kinetics, higher dose of G-CSF would be recommended when small children become donors for adult patients.

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan.

Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988-1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agents-unknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein-Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan-Meier analysis showed a 2-year event-free survival after SCT as 54.0+/-13.0%.

Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals.

Effects of YM-14673 (N alpha-[[S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate), a new TRH derivative, on reserpine-induced behavioural and electroencephalographic changes were observed in comparison with those of TRH. YM-14673 antagonized reserpine-induced hypothermia and decrease in convulsion threshold in mice. The number of PGO waves recorded from the lateral geniculate body was decreased by administration of YM-14673 in reserpinized cats. The anti-reserpine activity of intravenous YM-14673 was about 8-20 times more potent than that of TRH. In inhibiting reserpine-induced hypothermia, the oral ED2 degrees C relative to IV ED2 degrees C as an indirect indication of absorption rate of the drugs was 15 for both YM-14673 and TRH. These results suggest that YM-14673 possesses more potent facilitatory effects on the central monoamine systems than TRH.

Post-ischaemic treatment with orotic acid prevents neuronal injury in gerbil brain ischaemia.

We studied the effects of orotic acid, a precursor of pyrimidine nucleotide, on delayed neuronal death of hippocampal CA1 neurones induced by global cerebral ischaemia in Mongolian gerbils. Neuronal damage was significantly reduced in animals treated with orotic acid 2 h before ischaemia at doses of 100, 200 or 300 mg kg-1, i.p. A dose of 300 mg kg-1 given 24 h after ischaemia also suppressed CA1 neuronal damage, but had no effect when given at 48 or 72 h. These results demonstrate a protective effect of orotic acid on ischaemic neuronal damage with a wide therapeutic time window.

Analysis of growth failure in children treated for acute lymphoblastic leukemia.

Growth patterns were surveyed in 303 children with acute lymphoblastic leukemia who had remained in continuous first complete remission for a minimum of 1 year (median 3 years). Chemotherapy was given for 3 years, and central nervous system prophylaxis consisted of cranial irradiation at a total dose of 18 Gy or intravenous high-dose methotrexate (1.5-6 g/m2 for three to six doses). Intensive chemotherapy, including cyclophosphamide, doxorubicin, and cytosine arabinoside was given to children with high-risk features. Two of 205 children with low- or intermediate-risk features and 13 of 98 children with high-risk features showed a decrease in the growth rate of less than -2 SD. In 14 of these 15 patients, the age at onset was over 9 years and growth failure became most predominant in the prepubertal period: ten of these children showed a tendency toward delayed pubertal development, but eight showed later catch-up growth with pubertal maturation after completion of chemotherapy. Thus, chemotherapy appeared to contribute temporarily to the growth failure and gonadal impairment that occurred in the prepubertal period. No obvious correlation between the administered cranial irradiation and growth failure was found, but further study with a longer follow-up will be necessary to determine the long-term effects of irradiation on subsequent growth patterns in children.

Mutational analysis of the N-ras gene in acute lymphoblastic leukemia: a study of 125 Japanese pediatric cases.

A point mutation of the N-ras gene is one of the known genetic alterations identified in patients with acute lymphoblastic leukemia (ALL), but its clinical importance is still controversial. Using polymerase chain reactions, we examined codons 12, 13 and 61 of this gene in 125 Japanese childhood ALL patients (64 common-ALL, 22 pre-B-ALL, 33 T-ALL, 2 B-ALL, 3 undifferentiated ALL, and 1 unclassified ALL) including 9 relapsed patients. An N-ras point mutation was observed in 14 (11%) patients (9 common-ALL, 3 T-ALL, and 2 undifferentiated ALL; 13 patients at diagnosis and 1 at relapse). The patients with undifferentiated ALL harbored an N-ras mutation at a significantly higher rate. However, no correlation was found between the presence of an N-ras mutation and sex, age, or white blood count. There was no significant difference in the event-free survival rate between 13 fresh patients with an N-ras mutation and 103 patients with a wild-type configuration. The N-ras mutation was present in about 10% of childhood ALL cases but it did not have a prognostic impact. The sequence analyses revealed that the majority of the patients (13/14) had an N-ras mutation of a G to A transition. This finding was consistent with previous reports on N-ras mutations in acute leukemias in which the incidence of a G to A mutation was significantly higher in ALL than in myeloid malignancies.

Apolipoprotein E deposition and astrogliosis are associated with maturation of beta-amyloid plaques in betaAPPswe transgenic mouse: Implications for the pathogenesis of Alzheimer's disease.

A transgenic mouse expressing the human beta-amyloid precursor protein with the 'Swedish' mutation, Tg2576, was used to investigate the mechanism of beta-amyloid (Abeta) deposition. Previously, we have reported that the major species of Abeta in the amyloid plaques of Tg2576 mice are Abeta1-40 and Abeta1-42. Moreover, Abeta1-42 deposition precedes Abeta1-40 deposition, while Abeta1-40 accumulates in the central part of the plaques later in the pathogenic process. Those data indicate that Abeta deposits in Tg2576 mice have similar characteristics to those in Alzheimer's disease. In the present study, to understand more fully the amyloid deposition mechanism implicating Alzheimer's disease pathogenesis, we examined immunohistochemically the distributions of apolipoprotein E (apoE) and Abeta in amyloid plaques of aged Tg2576 mouse brains. Our findings suggest that Abeta1-42 deposition precedes apoE deposition, and that Abeta1-40 deposition follows apoE deposition during plaque maturation. We next examined the relationship between apoE and astrogliosis associated with amyloid plaques using a double-immunofluorescence method. Extracellular apoE deposits were always associated with reactive astrocytes whose processes showed enhancement of apoE-immunoreactivity. Taken together, the characteristics of amyloid plaques in Tg2576 mice are similar to those in Alzheimer's disease with respect to apoE and astrogliosis. Furthermore, apoE deposition and astrogliosis may be necessary for amyloid plaque maturation.