A new simple score (ABS) for assessing behavioral and psychological symptoms of dementia.

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This study was designed for a new simple assessment of BPSD. We first employed a clinical survey for the local community with sending an inquiry letter to all members (n=129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliability was examined comparing scores between main and second caregivers (n=70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r=0.716, **p<0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8s (**p<0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r=0.964, **p<0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

A mechanism for low penetrance in an ALS family with a novel SOD1 deletion.

BACKGROUND: About 20% of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in SOD1 and is typically transmitted as an autosomal dominant trait. However, due to reduced mutation penetrance, the disease may present in a recessive or sporadic manner. OBJECTIVE: To determine the factors responsible for the low penetrance of the SOD1 mutation. METHODS: Twelve members of a Canadian ALS family of Filipino origin were recruited for the study. SOD1 was sequenced in the proband. SOD1 expression was assessed by real-time-PCR and immunoblotting. RESULTS: The proband was a homozygous carrier of a novel 6 bp deletion in exon 2 (DeltaG27/P28), the pathologic significance of which was confirmed by immunohistochemistry. Eight living family members are heterozygotes and remain unaffected at ages ranging between 48 and 85 years. Haplotype analysis showed that the deletion is a single founder mutation likely common in the Cagayan province (Philippines). The low penetrance of the mutation is explained by the fact that it enhances the naturally occurring alternative splicing of exon 2 of the SOD1 mRNA, leading to reduced transcription of the mutant allele. Indeed, Western blot analysis demonstrated the low level of SOD1 protein in carriers of the DeltaG27/P28 compared to wild-type individuals or a carrier of the A4V SOD1 mutation. CONCLUSION: The enhanced splicing of exon 2 acts as a natural knock-down of the mutant SOD1 allele in the Filipino amyotrophic lateral sclerosis (ALS) family. There is a need for careful investigation of splicing isoforms of SOD1 and other ALS genes as factors influencing the severity of disease.

Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.

BACKGROUND: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). OBJECTIVE: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. METHODS: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. RESULTS: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. CONCLUSION: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

Mutational analysis of carbamoylphosphate synthetase I deficiency in three Japanese patients.

We describe the results of mutational analysis of the carbamoylphosphate synthetase I (CPSI) gene in three nonconsanguineous patients with CPSI deficiency. Compound heterozygotes of 3422T/G (V1141G) plus 3784C/T (R1262X), 1528delG (510-514 ARQLX) plus 2752T/C (S918P), and 2549G/A (R850H) plus 2797delT (L933X) were identified through genomic analysis; however, the 2797delT (L933X) mutation was not detected in cDNA analysis using biopsied liver, suggesting that mRNA expression rom this mutant allele is absent or markedly low.

Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients.

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.

Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease.

OBJECTIVE: To describe a novel missense mutation, Asp678Asn (D678N), in the amyloid precursor protein (APP) gene in a Japanese pedigree of probable familial Alzheimer's disease (FAD). SUBJECT: The proband was a women of 72. Symptoms of dementia that fulfilled the criteria for probable Alzheimer's disease appeared at about 60 years of age, and slowly worsened over more than 10 years without evident cerebrovascular complications, either clinically or neuroradiologically. METHODS: Polymerase chain reaction single strand conformational polymorphism (PCR-SSCP) analysis followed by sequence analysis was used to examine genomic DNA of the proband for mutations in the APP gene exons 16 and 17. RESULTS: Analysis of the APP exon 16 in the proband showed a GAC to AAC nucleotide substitution in codon 678 of the APP gene, causing an amino acid substitution of Asp to Asn (D678N). Heterozygosity of the APP D678N mutation was found in the proband and in the demented elder sister. CONCLUSIONS: The production and accumulation of mutated Abeta (Asn7-Abeta) or the misfunction of D678N mutant APP may have pathogenic properties for the development of Alzheimer's disease in this pedigree.

[Causative genes in Alzheimer's disease].

Recently, some Alzheimer-associated genes have been found: amyloid precursor protein (APP), apolipoprotein E (apoE), presenilin 1 (PS-1) and presenilin 2 (PS-2). First, we examined mutations of APP, PS-1, and PS-2 genes in familiar Alzheimer's disease (FAD) (7 cases) found in San-in district by single-strand conformation polymorphism and sequence analysis. These seven cases with FAD did not show any mutations of APP, PS-1, and PS-2 genes. Other susceptibility genes of FAD still remain to be not identified. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheier's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphisms of the ER alpha gene may be a genetic risk factor for SAD. The apoE genotype is a genetic factor closely related SAD, but it is not full by appreciated how apoE has an effect on developing AD. There are few reports on the quantitative change of apoE, namely the expression of apoE mRNA. Third, ApoE mRNA level in the brains of patients with Alzheimer's disease (27 cases) and Down's syndrome (11 cases) was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ApoE mRNA level in the DS as well as AD was significantly higher than that in control group (p < 0.05, p < 0.05, respectively). High levels of apoE mRNA in AD and DS may play an important role in the development of Alzheimer pathology.

Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy.

Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P<0.001) and those in CTL (P<0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P<0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P<0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P=0.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.

[A case of late-onset carbamoyl phosphate synthetase I deficiency, presenting periodic psychotic episodes coinciding with menstrual periods].

Carbamoyl phosphate synthetase I deficiency (CPSID) is a rare metabolic disorder affecting the first enzymatic step of urea cycle. We report clinical manifestations of a female case of late-onset CPSID in Japan. An 18-year-old girl was admitted to emergency room due to acute comatose state. Her parents had no apparent consanguineous history. She had suffered from intermittent psychotic episodes (excitation, aggressive behavior and insomnia) with nausea and vomiting from the age of 13, mostly coinciding with menstrual period. She had minor learning disability without major neurological deficits and convulsions. Her mental status was estimated as normal in her intermenstrual period. She had been diagnosed as having hysteria and premenstrual syndrome. Her neurological findings on admission showed deep coma and hypotonic tetraparesis. Plasma ammonia level was markedly elevated (684 micrograms/dl) without significant liver dysfunction. Blood urea nitrogen decreased to 6 mg/dl. Continuous venovenous filtration with subsequential administration of sodium benzoate and l-arginine was started to eliminate blood ammonia. Although the plasma ammonia level decreased to 300 mu/dl in next 10 hours, severe cerebral edema was observed in head computed tomography subsequently, followed by marked cerebral atrophy. Finally, her consciousness status became almost alert a month after the onset, but her mental status was severely retarded. CPSI activity of her biopsied liver markedly decreased and she was diagnosed as having CPS ID. CPSI cDNA analysis of her biopsied liver demonstrated a V1149G mutation. Genomic DNA analysis showed that she was heterozygous in V1149G mutation. The mutation allele was derived from her father. The causative factor for absence or very low level of maternal CPSI mRNA will require further analysis.

[Analysis of causative genes and genetic risk factor in Alzheimer's disease].

Recently, some Alzheimer-associated genes have been found: amyloid beta protein precursor (APP), apolipoprotein E (apoE), presenilin 1 (PS-1), and presenilin 2 (PS-2). First, we failed to discover other susceptibility genes of familial Alzheimer's disease (FAD). However, we disClosed a novel mutation. Asp678Asn (D678N), in the APP gene in a pedigree of early-onset Japanese FAD. The alteration in the aggregation properties of mutant A beta may be involved in the pathogenesis of FAD with D678N APP mutation. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheimer's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphism of the ER alpha gene may be a genetic risk factor for SAD.

[A case of superior sagittal sinus thrombosis following long-term medication with carbamazepine].

A 55-year-old man, who had been medicated with carbamazepine, phenobarbital, and sodium valproate for 12 years' duration, presented with severe headache, nausea, and transient diplopia. The neurological examination revealed mild disturbance of consciousness and postural tremor. He also complained of severe continuous headache but no throbbing pain. Enhanced head CT showed empty delta sign and irregular pooling of contrast agent around the superior sagittal sinus. Head MRI did not show the flow void in the superior sagittal sinus. Cerebral angiography demonstrated incomplete occlusion of the superior sagittal sinus and well-developed colateral channels. He was diagnosed having superior sagittal sinus thrombosis, and was placed on anticoagulant and antiplatelet drugs. He did not have any other risk factors such as inflammatory disease, infection, malignancy, and oral contraceptives. However, he had been medicated with some anticonvulsants including carbamazepine, which is known to induce venous thrombosis in the leg. Therefore, the association between superior sagittal sinus thrombosis and long term medication with carbamazepine was suspected. This is the first case report of anticonvulsant-associated cerebral venous thrombosis. It suggests that long-term medication with carbamazepine should be considered to be one of the risk factors for cerebral venous thrombosis.

The expression of presenilin 1 mRNA in skin fibroblasts and brains from sporadic Alzheimer's disease.

We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer's disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.

Lipoprotein(a) phenotypes in patients with vascular dementia.

We tried to examine if there is a particular distribution pattern of lipoprotein(a) [Lp(a)] phenotypes specific for patients with vascular dementia (VD). Fourteen cases of VD (9 males and 5 females), 18 cases of dementia of the Alzheimer type (DAT)(7 males and 11 females), 29 cases of cerebrovascular disease (CVD) in the chronic phase (18 males and 11 females) and 47 healthy individuals as controls (25 males and 22 females) were examined for serum Lp(a). Serum concentrations and phenotypes of Lp(a) were assessed by ELISA and a test kit for the Lp(a) phenotype, respectively. Serum concentrations of Lp(a) were significantly higher in patients with VD (p < 0.05) as well as patients with CVD (p < 0.01) compared with those in healthy individuals. Serum concentrations of Lp(a) did not significantly differ between patients with DAT and healthy individuals. The incidences of Lp(a) phenotypes containing relatively low-molecular-weight apolipoprotein(a) isoforms were significantly higher in patients with CVD in the chronic phase (p < 0.05) or those with VD (p < 0.01) compared with those in healthy individuals. Distribution patterns of Lp(a) phenotypes did not differ between patients with DAT and healthy individuals. Thus, high serum levels of Lp(a) could be considered a clinical hallmark to distinguish VD from DAT. Abnormally high serum levels of Lp(a) in patients with CVD and VD seemed to be due to specific increases in low-molecular-weight apolipoprotein(a) isoforms in Lp(a).

Alteration in brain presenilin-1 mRNA expression in sporadic Alzheimer's disease.

Expression of presenilin-1 (PS-1) mRNA in an alternative splicing at the 3' end of exon 3 was examined in brain tissue, lymphocytes and cultured skin fibroblasts using the RT- polymerase chain reaction (RT-PCR) method. We quantified the relative ratios of the densities of the long form of PS-1 mRNA, which contains a sequence encoding four amino acids (VRSQ, denoted as VRSQ+) to the short form, which lacks the VRSQ sequence (VRSQ-). The brain tissue of subjects with sporadic Alzheimer's disease (AD) had reduced levels of the VRSQ+ form of the PS-1 mRNA compared to a control group. No significant differences appeared in peripheral tissues, such as lymphocytes or cultured skin fibroblasts in AD with control subjects. Changes in the alternative splicing of exon 3 may be specific to the brain and may play an important role in the pathogenesis of sporadic AD.

Epidemiologic and genetic studies of dementia of the alzheimer type in japan.

We carried out two separate epidemiological studies on long-term changes, 10 years apart, on the prevalence rate of dementia in the elderly by the same method for the same area in Japan. We also performed a genetic study of patients with dementia of the Alzheimer type (DAT) based on the epidemiological studies. The number of patients with dementia was much larger in 1990 than in 1980. Especially, the number of mildly demented patients was significantly larger in 1990 than in 1980. The 35 patients with DAT did not show any mutations of amyloid-beta protein precursor, presenilin 1 and presenilin 2 genes. The frequency of apolipoprotein E (apo E) sigma4 allele in DAT was significantly higher than that in control subjects (p < 0.005). This study suggests that the frequency of DAT may increase by aging of the population in the future and we confirm the close association between apoE sigma4 allele and DAT in a community-based study in Japan.