Clinical assessment and prevalence of parkinsonism in Japanese elderly people.

BACKGROUND: Parkinsonism is often observed in the elderly. To clarify the prevalence of parkinsonism-associated diseases and conditions, we conducted a population-based study in a rural island town in western Japan, Ama-cho. METHODS: Participants included 924 subjects aged 65 years or older residing in the town. Between 2008 and 2011, participants were assessed via standardized neurological examination scales, and Brain MRIs were carried out in 2010. Based on the results of assessment using the modified Unified Parkinson's Disease Rating Scale and a standardized neurological examination, participants were diagnosed as having parkinsonism or mild parkinsonian signs (MPS), or as displaying normal motor conditions (M-normal). RESULTS: Of the 729 participants screened, 70 subjects were diagnosed as having parkinsonism, corresponding to a crude prevalence rate of 9.6% (95% CI, 7.9-11.3%), while 167 MPS subjects (22.9%) and 492 subjects experiencing M-normal (67.5%) were observed. Parkinsonism was found in association with various diseases such as Vascular parkinsonism, Lewy body disease, Alzheimer's disease (AD), and idiopathic normal-pressure hydrocephalus. Among the subjects with dementia, the proportion with parkinsonism was higher in the non-AD dementia group. CONCLUSION(S): Parkinsonism occurs in association with several diseases in elderly people. Parkinsonism was also found to be commonly associated with cognitive impairment.

Depression and cognitive impairment in patients with mild parkinsonian signs.

OBJECTIVES: Mild parkinsonian signs (MPS) are reported to be associated with increased risk of dementia, Parkinson's disease, parkinsonism, and vascular lesions of white matter and are also a significant predictor of mortality. Although more than 20% of subjects aged 60 years and older suffer from MPS in Japan, it is often unrecognized and underestimated by patients and medical physicians. We used neuropsychological methods to examine cognitive function and depressive symptoms in subjects with MPS. METHODS: We performed a population-based study in Ama-cho, a rural island town in western Japan. Participants included 951 subjects aged 65 years and older, 613 of whom completed all questionnaires, neurological examinations, and neuropsychological assessments and were included in the data analysis. Subjects were assessed for depression and subjective cognitive impairment using the Geriatric Depression Scale (GDS-15), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and modified Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: Of the 613 participants, 143 were diagnosed with MPS. GDS scores were significantly higher in the MPS group compared with the motor control group, while MMSE scores were significantly lower. CONCLUSIONS: We demonstrated that MPS correlate with both depressive symptoms and cognitive impairment.

Assessment of dementia in patients with multiple system atrophy.

BACKGROUND AND PURPOSE: We investigated dementia in patients with multiple system atrophy (MSA) in order to characterize the prevalence and nature of impairments in these patients. METHODS: Fifty-eight MSA patients were recruited in our institution between April 1996 and December 2006 and investigated. RESULTS: Of 58 patients, 10 were diagnosed with dementia. There were no significant differences in age at onset, gender, duration of disease, or severity of cerebellar dysfunction between patients with and without dementia. The early and delayed heart to mediastinum (H/M) ratios obtained with (123)I-metaidobenylguanidine (MIBG) cardiac scintigraphy were significantly decreased in patients with dementia compared with those without dementia. Of the 10 patients with dementia, three were found to have cognitive decline that preceded onset of motor symptoms. White matter lesions were evident in these patients, whilst frontal atrophy was prominent in patients whose cognitive decline was preceded by onset of motor symptoms. CONCLUSIONS: Dementia in patients with MSA may be more common than previously thought, furthermore, we speculate that clinical features of dementia in these patients might be heterogeneous.

Epidemiological study of acute encephalitis in Tottori Prefecture, Japan.

BACKGROUND AND PURPOSE: To conduct an epidemiological survey of acute encephalitis focusing on non-herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. METHODS: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. RESULTS: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service-based incidence rate of acute encephalitis was 19.0 per million person-years. The incidence rate of NHALE subtype was 4.7 per million person-years. CONCLUSIONS: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.

Assessment of hallucinations in Parkinson's disease using a novel scale.

OBJECTIVE: To assess hallucinations in Parkinson's disease (PD), we developed a novel practical rating scale that evaluates five items including variety, frequency, and severity of hallucinations, caregiver burden levels, and psychiatric status at nighttime. METHODS: Forty-one PD patients and their caregivers were examined regarding the status of the hallucinations associated with PD. RESULTS: As a measure of internal consistency, the Tottori University Hallucination Rating Scale (TUHARS) has a Cronbach's alpha of 0.88. Mini-Mental State Examination (MMSE) and Hoehn-Yahr stage were associated with the TUHARS scores in a multivariate regression analysis. Visual hallucinations are the most common. However, half of the patients who reported visual hallucinations also had other hallucinations. The scale scores in the PD patients with dementia (PDD) group were significantly greater than in the PD patients without dementia (PDnD) group. CONCLUSIONS: TUHARS appears to be a suitable and easily administered instrument for assessment of hallucinations in PD. PD patients experienced various kinds of hallucinations. Hallucinations may have a close relationship with cognitive decline in PD patients.

Executive dysfunction in non-demented Parkinson's disease patients with hallucinations.

OBJECTIVE: We investigated executive function in Parkinson's disease (PD) patients, and focused on executive dysfunction in PD with hallucinations, but without dementia. METHODS: PD patients were classified by cognitive or neuropsychotic status as PD group, PD with vivid dreaming group, PD with hallucinations group and Parkinson's disease dementia (PDD) group. Psychomotor speed tests, the Stroop test, a verbal fluency test and the Self-rating Depression Scale were performed. RESULTS: The PDD group showed poorer scores in every test compared with the PD group. The PD with hallucinations group showed results similar to those of the PDD group, while the PD with vivid dreaming group was similar to the PD group. CONCLUSIONS: The study suggests that PD patients with hallucinations, not extensive enough to qualify as dementia, already have executive dysfunction similar to that seen in PDD patients. Executive dysfunction may be an important substrate for hallucinations even when dementia is not yet apparent.

Serum proteomic profiling of dementia with Lewy bodies: diagnostic potential of SELDI-TOF MS analysis.

Dementia with Lewy bodies (DLB) is the second most common senile degenerative dementia after Alzheimer's disease (AD). The presentation of overlapping symptoms between these two disorders leads to difficulties in the determination of clinical entities. Serum samples were subjected to surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) analysis in order to identify a diagnostic marker for DLB. Four putative protein peaks (m/z 3,883, 4,964, 7,761 and 10,534) were differentially expressed in DLB patients compared to AD patients and control subjects. Receiver operating characteristics (ROC) analysis of a multivariate logistic model of the combination of three peaks (m/z 3,883, 7,761 and 10,534) exhibited the highest discriminatory ability of DLB subjects from non-DLB subjects with a sensitivity of 83.3%, a specificity of 95.8%, a positive predictive value of 90.9% and a negative predictive value of 92.0%. SELDI-TOF MS profiling, therefore, has revealed a serum signature with high diagnostic potential for DLB.

Clinical evaluation of Parkinson's disease dementia: association with aging and visual hallucination.

OBJECTIVES: In order to explore factors associated with the development of dementia in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), we systematically investigated the clinical evaluation of PD and DLB patients hospitalized in the Department of Neurology at Tottori University Hospital, Japan. RESULTS: There were 208 patients diagnosed as having PD and 39 patients diagnosed with DLB in this study. Of the patients with PD, 67 (32%) developed dementia and only five PD+ patients were considered to have cognitive impairment attributable to Alzheimer's disease (AD) or vascular dementia (VaD). Fifty-four (81%) PDD patients had visual hallucinations (VH) with or without cognitive fluctuation. The onset age of parkinsonian motor symptoms of patients with PD dementia (PDD) did not differ from that of PD patients without dementia. There was a significant inverse correlation between the onset age of motor symptoms in PD and the onset of their dementia in PDD. Seventy-five (36%) patients with PD had experienced VH and most of the PDD patients had experienced VH within 1 year before or after diagnosis of PDD. CONCLUSIONS: These results indicate that aging and VH are important factors associated with dementia in PD.

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.

[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.

Estrogen receptor gene polymorphisms in patients with Alzheimer's disease, vascular dementia and alcohol-associated dementia.

The association between the estrogen receptor (ER-alpha) gene and dementia was examined in 223 patients with Alzheimer's disease (AD), 66 with vascular dementia (VD), 17 with alcohol-associated dementia (ALD) and 134 healthy elderly control subjects. The PvuII and XbaI restriction fragment length polymorphisms of the ER-alpha gene were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of restriction sites and small letters the presence of restriction sites. We found that the frequency of the ER-alpha gene P allele and X allele in the late-onset AD (LOAD) group (P allele was 0.51, X allele was 0.30) was significantly higher than that in controls (P 0.38, p < 0.01; X 0.20, p < 0.01), and that the frequency of the ER-alpha gene P allele and PP genotype was significantly different between apolipoprotein E epsilon4 carriers and noncarriers in LOAD. These findings suggest that the genotype of the ER-alpha gene may be specific in LOAD, and that the ER-alpha gene was an additional risk for LOAD.

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).