Tooth Loss-associated Cognitive Impairment in the Elderly: A Community-based Study in Japan.

Objective Dementia is a major cause of disruption for a healthy life expectancy in Japan. It has been suggested that the number of teeth is a modifiable risk factor for cognitive impairment and dementia. We therefore examined the possible association between the cognitive function and the number of natural and artificial teeth in community-dwelling Japanese elderly individuals. Methods Among the participants in our prospective, community-based study, 210 elderly individuals (103 men and 107 women; 78.1±4.9 years; mean age±standard deviation) underwent both dental examinations and a Mini-Mental State Examination (MMSE), as well as various medical checkups, in 2016 and 2017. Results The number of natural teeth was significantly associated with an individual's MMSE score. The percentage of cognitively normal subjects (MMSE scores: 27-30) decreased significantly with a decrease in the number of natural teeth. Among the MMSE items, the calculation ability was significantly and independently associated with the number of natural teeth. Regression was calculated as the predicted score of MMSE =21+0.3× (years of schooling) +0.1× (number of natural teeth). Among individuals with 19 or fewer natural teeth, those who had a total of 20 teeth or more, including both natural and artificial teeth, had significantly higher MMSE scores than those who had 19 or fewer natural and artificial teeth combined. Conclusion The number of natural teeth was significantly associated with the cognitive function, especially the calculation ability, and the use of artificial teeth was associated with the preservation of the cognitive function in community-dwelling elderly individuals.

Clinical and radiological diversity in genetically confirmed primary familial brain calcification.

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.

Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders.

BACKGROUND: Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult. CASE PRESENTATION: We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth-based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change. CONCLUSION: It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders.

A Segmental Copy Number Loss of the SFMBT1 Gene Is a Genetic Risk for Shunt-Responsive, Idiopathic Normal Pressure Hydrocephalus (iNPH): A Case-Control Study.

Little is known about genetic risk factors for idiopathic normal pressure hydrocephalus (iNPH). We examined whether a copy number loss in intron 2 of the SFMBT1 gene could be a genetic risk for shunt-responsive, definite iNPH. Quantitative and digital PCR analyses revealed that 26.0% of shunt-responsive definite iNPH patients (n = 50) had such a genetic change, as compared with 4.2% of the healthy elderly (n = 191) (OR = 7.94, 95%CI: 2.82-23.79, p = 1.8 x 10-5) and 6.3% of patients with Parkinson's disease (n = 32) (OR = 5.18, 95%CI: 1.1-50.8, p = 0.038). The present study demonstrates that a copy number loss within intron 2 of the SFMBT1 gene may be a genetic risk factor for shunt-responsive definite iNPH.

Inflammatory Pseudotumor of the Brain Parenchyma with IgG4 Hypergammaglobulinemia.

A 58-year-old woman with a 1-month history of right hand clumsiness and speaking difficulty was admitted to our hospital. A neurological examination revealed sensory aphasia and right hemiparesis. Her laboratory tests showed elevated serum levels of IgG and IgG4, pancytopenia, and liver dysfunction. The results of the imaging studies of her abdomen were compatible with sclerosing cholangitis. Brain MRI showed extensive signal abnormalities in the left hemisphere on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, extending from left internal capsule to the cerebral peduncle with an irregularly enhancing lesion in the left parietal lobe. A brain biopsy revealed lymphocyte and plasma cell infiltration and reactive gliosis. Most of the plasma cells were IgG positive; however, IgG4-positive plasma cells were sparsely observed. After the initiation of betamethasone treatment, her symptoms and the brain MRI abnormalities showed significant improvement. The brain biopsy results did not meet the current criteria of IgG4-related disease. This is the first reported case of a tumefactive lesion of the brain parenchyma with serum IgG4 elevation, which was responsive to steroid treatment. The accumulation of a greater number of reports on the pathological investigation of cases of possible IgG4-related disease may help to elucidate the exact role of IgG4 in IgG4-related disorders.

Impact of nocturnal heart rate variability on cerebral small-vessel disease progression: a longitudinal study in community-dwelling elderly Japanese.

Recent evidence has shown an effect of ambulatory heart rate (HR) on cardiovascular events and mortality. Our objective was to determine whether ambulatory HR was related to the progression of cerebral small-vessel disease (SVD) or cognitive decline in community-dwelling elderly people. A cohort of 190 community-dwelling elderly people underwent an ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI) and cognitive testing at baseline, with MRI and cognitive tests repeated 4 years later. HR variability in ABPM was quantified by the s.d. (s.d. and the root mean square of successive differences (RMSSD), and the relationship between HR variability and the progression of SVD/cognitive decline was investigated. We also assessed the association of nighttime HR variability and nocturnal HR dipping. The nighttime RMSSD of participants with the progression of SVD was significantly higher than that of those without progression of SVD (P<0.05). Moreover, nighttime RMSSD was independently associated with the progression of SVD (1 b.p.m. increment: odds ratio=1.13, 95% confidence interval=1.04-1.24, P<0.01). We failed to confirm an association between cognitive decline and nighttime HR variability. However, s.d. in the daytime and 24-h HR were independently related to cognitive decline (P<0.05). Nocturnal HR dipping was least in the top quartiles of nighttime HR variability, with a monotonic trend of nocturnal HR dipping that was dependent on the quartiles of nighttime HR variability indices (P<0.01). Increased HR variability during the night is a predictor of the progression of SVD in community-dwelling elderly people.

Change of carotid intima-media thickness is associated with age in elderly Japanese patients without a history of cardiovascular disease.

AIM: The present study aimed to evaluate the relationship between the change of carotid intima-media thickness (CIMT) and clinical characteristics in Japanese patients without a history of cardiovascular disease. METHODS: The study participants were 149 Japanese patients without a history of cardiovascular disease treated in our outpatient department. The in all participants CIMT was measured with ultrasonography at baseline and after a mean interval of 2.4 years. Study participants were divided into a middle-aged group (younger than 65 years: n = 59) and an elderly group (65 years or older: n = 90). The annual CIMT change (ΔCIMT) was calculated, and the associations between ΔCIMT and clinical characteristics, including age, were evaluated in both groups. RESULTS: The ΔCIMT was significantly correlated with age in all participants (r = 0.222; P < 0.05) and in elderly participants (r = 0.234; P < 0.05), but was not correlated with other risk factors. The annual ΔCIMT was significantly higher in elderly participants (0.015 ± 0.096 mm) than in middle-aged participants (-0.018 ± 0.088 mm; P < 0.05). Multivariate linear regression analysis with ΔCIMT as a dependent variable and risk factors as independent variables showed that ΔCIMT was significantly associated with age in all participants (ß = 0.002; P < 0.05) and in elderly participants (ß = 0.004; P < 0.05), but not with other risk factors. CONCLUSIONS: Annual CIMT change is associated with age, rather than with other clinical characteristics, including traditional cardiovascular risk factors, such as diabetes and hypertension, in elderly Japanese patients without a history of cardiovascular disease.

Clinical significance of mammillary body enhancement in Wernicke encephalopathy: report of 2 cases and review of the literature.

In 2 cases of Wernicke encephalopathy in which the initial symptom was double vision, the only abnormal finding on magnetic resonance (MR) imaging was abnormal enhancement of the mammillary bodies. The mammillary bodies are the region most vulnerable to abnormal enhancement. Because MR imaging with contrast enhancement can detect such abnormal enhancement at an early stage, it should be performed more often in patients with oculomotor disorders to avoid underdiagnosis of Wernicke encephalopathy.

Impact of ambulatory blood pressure variability on cerebral small vessel disease progression and cognitive decline in community-based elderly Japanese.

BACKGROUND: Recent epidemiological studies reported a relationship between 24-hour ambulatory blood pressure (ABP) variability and cardiovascular events. However, the impact of ABP variability on small vessel disease (SVD) progression or cognitive decline in the elderly has seldom been investigated in community-based longitudinal studies. METHODS: Subjects (n = 210) underwent ABP monitoring, brain magnetic resonance imaging (MRI), and cognitive testing at baseline and 4 years later. ABP variability was quantified by the SD, weighted SD, coefficient of variation (CV), and average real variability (ARV). ABP variability parameters were divided into 2 groups by median values. RESULTS: Multivariable logistic regression analyses showed that higher systolic CV, diastolic weighted SD, and diastolic CV were significant predictors of SVD progression (P = 0.02, 0.03, and 0.02, respectively). In subjects with SVD on the first MRI, higher systolic and diastolic ARV also predicted progression (P = 0.04 and 0.03, respectively). Higher quartiles of systolic weighted SD and CV had higher incidences of SVD progression (P trend = 0.03 and 0.03, respectively, Cochran-Armitage test), and higher quartiles of systolic ARV had higher incidences of SVD progression in subjects with SVD on the first MRI (P trend = 0.03). Higher systolic ARV was an independent predictor of cognitive decline (P < 0.01), and higher tertiles of systolic ARV had higher incidences of cognitive decline (P trend = 0.02). CONCLUSIONS: This community-based longitudinal study found that increased ABP variability was associated with SVD progression, particularly in individuals with SVD at baseline. Higher systolic ARV predicted SVD progression and cognitive decline.

Incidence of idiopathic normal pressure hydrocephalus (iNPH): a 10-year follow-up study of a rural community in Japan.

BACKGROUND: The epidemiology and pathophysiology of iNPH remain unclear. We aimed to investigate the incidence of iNPH in elderly inhabitants of the community, and to identify how ventriculomegaly develops on brain MRIs and how symptoms develop in iNPH patients. METHODS: In 2000, 350 inhabitants, all 70-year-olds living in the community of Takahata in Japan, were asked to participate in a survey that included a questionnaire, physical examinations, cognitive screenings, and brain MRI studies. Using brain MRI as a screening, we defined having both Evans index of >0.3 and a narrow subarachnoid space and cortical sulci at high convexity (tight high convexity, THC) as suspicious findings for iNPH. Among the subjects who showed the iNPH feature on brain MRI, those who had gait disturbance and/or dementia were defined as possible iNPH. Twice during the 10 years, we administered the same check-up. RESULTS: In the first survey, 271 inhabitants participated. During the 10 years, three new possible iNPH patients were found. The incidence of iNPH above 70 years old was estimated at 1.2/1000 persons per year. The iNPH patients developed their symptoms and brain MRI findings as follows; first, only THC without ventriculomegaly was observed on their brain MRIs, next, asymptomatic ventriculomegaly with features of iNPH on brain MRIs (AVIM) was seen, and then a final expression of symptoms of iNPH was shown. CONCLUSIONS: The estimated incidence of iNPH in a community was higher than those estimated by previous studies where they collected patients at hospitals. There were subclinical or preclinical states before the development of iNPH.

Chronic headaches and sleepiness caused by facial soap (containing hydrolyzed wheat proteins)-induced wheat allergy.

A 38-year-old woman was suffering from irregular headaches and sleepiness. She had used soap containing Glupearl 19S (hydrolyzed wheat proteins) every day for approximately one year and had experienced an episode of rash eruption on her face seven months ago. Wheat-specific IgE antibodies were detected in her serum. A Western blot analysis revealed a high titer of IgE antibodies against Glupearl 19S and wheat proteins. The patient was sensitive to these compounds in a skin prick test. After avoiding eating wheat, her headaches and sleepiness disappeared. A hidden food allergy is a possible cause of these symptoms.

Neuromyelitis optica preceded by hyperCKemia and a possible association with coxsackie virus group A10 infection.

We report the case of a 48-year-old woman presenting with an elevated serum creatine kinase level (hyperCKemia) associated with an initial attack of neuromyelitis optica (NMO). The patient initially showed general fatigue with fever. Laboratory findings showed hyperCKemia and subsequently she developed a slight weakness of both lower limbs and reduced vision. Autoantibodies against aquaporin 4 were found in her serum, and a retrospective examination of viral titers indicated a possible coxsackie virus group A10 infection. The present case suggests that hyperCKemia-mediated disease onset is involved in some patients with NMO, and furthermore, it may be related to muscular destruction associated with viral infection.

Lymphomatosis cerebri with intramedullary spinal cord involvement.

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma (PCNSL). Little is known about cases of LC with spinal cord involvement. Among the 11 PCNSL patients treated in our hospital during a four-year period, we identified two cases of LC with spinal cord lesions. One showed a spinal cord lesion followed by leukoencephalopathy. The other showed a spinal cord lesion after LC. In both cases, the histopathology was diffuse large B-cell lymphoma. It is possible that LC may affect the entire central nerve system, and tumor infiltration to the brain and spinal cord in LC may occur more frequently than has been previously considered.

Subclinical declines in the verbal fluency and motor regulation of patients with AVIM (asymptomatic ventriculomegaly with features of idiopathic NPH on MRI): a case-controlled study.

OBJECTIVE: We previously reported that, on brain MRI, iNPH features were observed in approximately 1% of asymptomatic elderly community dwellers. This phenomenon is designated asymptomatic ventriculomegaly with features of iNPH on MRI (AVIM). The aim of the present study was to clarify whether a subclinical decline in the neuropsychological function is present in patients with AVIM. METHODS: We examined eight subjects with AVIM, six subjects with possible iNPH and 21 elderly controls. Neuropsychological tests were used, including the mini-mental state examination (MMSE), the Hasegawa dementia scale-revised (HDS-R), the frontal assessment battery (FAB), the trail making test A&B and semantic and letter verbal fluency tests. RESULTS: When comparing the individuals with AVIM with the control subjects, significant differences were found in the scores achieved on the semantic verbal fluency tests and Luria's motor series (fist-edge-palm), a subtest of the FAB. CONCLUSION: The present study suggests that individuals with AVIM demonstrate a slight subclinical decline in the cognitive function and motor regulation, which may represent a prodromal stage of iNPH.

Steroid-responsive thalamic lesions accompanying microbleeds in a case of Hashimoto's encephalopathy with autoantibodies against α-enolase.

A 67-year-old man receiving antithrombotic therapy developed rapidly progressive amnesia. T2-weighted images of brain MRI revealed hyperintense lesions in the bilateral thalami accompanied by microbleeds. Antithyroglobulin antibodies and autoantibodies against the N-terminal of α-enolase (NAE) were identified in the patient's serum; therefore, Hashimoto's encephalopathy (HE) was suspected. Although the patient's radiological findings improved following steroid therapy, his symptoms did not improve, possibly due to increased thalamic microbleeds. Because anti-NAE antibodies are possibly associated with vasculitis, HE accompanied by anti-NAE antibodies may be exacerbated by microbleeds in patients receiving antithrombotic therapy.

Comparison of caregiver strain in Parkinson's disease between Yamagata, Japan, and Maryland, The United States.

BACKGROUND: Japan and the United States (US) have different cultures of caregiving including differences in family structure and social programs that may influence caregiver strain. Differences in caregiver strain between regions in Japan and in the US have not been investigated in patient-spouse dyads in PD. OBJECTIVES: To compare caregiver strain in spouses of PD patients between Yamagata, Japan and Maryland, US. Correlations between caregiver strain and patient/spousal variables are also examined. METHODS: In Yamagata and Maryland, spouses of patients with PD completed questionnaires assessing caregiver strain. Patients and spouses completed scales assessing mental health, and medical co-morbidity. PD severity and disability were assessed with the Unified Parkinson's Disease Rating Scale and the Schwab and England Activities of Daily Living Scale. Results in the two regions were compared with Chi-square and Student's t-tests. Relationships between caregiver strain and patient/spousal variables were analyzed with univariate correlations and multivariate regression. RESULTS: 178 Spouse-patient pairs were assessed. The level of caregiver strain in PD did not differ between Yamagata, Japan and Maryland, US despite differences in demographics and social support programs in the two regions. Yamagata spouses reported physical, time and financial constraints, while Maryland spouses reported more emotional distress. In both regions, spousal depression was a significant contributor to caregiver strain. CONCLUSION: Different approaches to reduce caregiver strain will likely be necessary in Yamagata and Maryland since the contributing factors to caregiver strain are influenced by differences in culture and social supports in each country.

Marked improvement in opsoclonus and cerebellar ataxia after the surgical removal of a squamous cell carcinoma of the thymus: a case report.

A 69-year-old man with rapidly evolving vertigo and ataxia was admitted to our hospital. He was presented with a dysarthric speech and chaotic eye movements, identified as opsoclonus. Neurological examination revealed limb and truncal ataxias and an inability to stand unless fully assisted. A chest CT scan revealed a mass at the anterior mediastinum, which suggested paraneoplastic neurological syndrome (PNS). However, an extensive search for anti-neuronal antibodies linked to cerebellar ataxia failed to find any autoantibodies, including cell surface autoantibodies. Subsequently, a total surgical removal of the thymic tumor was performed, leading to marked improvements in his signs and symptoms. The pathological findings by conventional and immunohistochemical examinations confirmed a squamous cell carcinoma of the thymus. Three months after onset his signs and symptoms improved and he was able to walk without support. In contrast to thymomas, PNS is extremely rare in patients with thymic carcinoma. Previous reports have shown that neurological symptoms, similar to opsoclonus or cerebellar ataxia, deteriorated in cases of thymic carcinoma that could not be controlled. The present report indicates that early diagnosis and total removal of the rare neoplasm may increase the possibility of neurological recovery.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

Epidemic myalgia in adults associated with human parechovirus type 3 infection, Yamagata, Japan, 2008.

Human parechovirus has rarely been shown to cause clinical disease in adults. During June-August 2008, a total of 22 adults sought treatment at Yonezawa City Hospital in Yamagata, Japan, for muscle pain and weakness of all limbs; most also had fever and sore throat. All patients received a clinical diagnosis of epidemic myalgia; clinical laboratory findings suggested an acute inflammatory process. Laboratory confirmation of infection with human parechovirus type 3 (HPeV3) was made for 14 patients; we isolated HPeV3 from 7 patients, detected HPeV3 genome in 11, and observed serologic confirmation of infection in 11. Although HPeV3 is typically associated with disease in young children, our results suggest that this outbreak of myalgia among adults was associated with HPeV3 infection. Clinical consideration should be given to HPeV3 not only in young children but also in adults when an outbreak occurs in the community.

UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family.

The causal gene(s) for familial adult myoclonic epilepsy (FAME) remains undetermined. To identify it, an exome analysis was performed for the proband in a Japanese FAME family. Of the 383 missense/nonsense variants examined, only c.5720G>A mutation (p.Arg1907His) in the UBR5 gene was found in all of the affected individuals in the family, but not in the nonaffected members. Such mutation was not found in any of the 85 healthy individuals in the same community nor in any of the 24 individuals of various ethnicities. The present study demonstrated an FAME-associated mutation in the UBR5 gene, which is located close to the reported locus linked to Japanese FAME families.