FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.

Association of Modifiable Lifestyle Factors With Cortical Amyloid Burden and Cerebral Glucose Metabolism in Older Adults With Mild Cognitive Impairment.

Importance: Understanding the association of lifestyle factors with mild cognitive impairment enables the development of evidence-based interventions for delaying cognitive impairment. Objective: To explore whether objectively measured lifestyle factors, such as physical activity, conversation, and sleep, are associated with cortical amyloid burden and cerebral glucose metabolism in older adults with mild cognitive impairment. Design, Setting, and Participants: This cohort study included 855 community-dwelling adults in Usuki, Oita Prefecture, Japan, aged 65 years or older. Data were collected from August 2015 to December 2017. Participants were reviewed to examine risk and protective lifestyle factors for dementia. Data analysis was conducted in June 2019. Exposures: Wearable sensors, carbon-11 labeled Pittsburgh compound B positron emission tomography images, and fluorine-18 fluorodeoxyglucose positron emission tomography images. Main Outcomes and Measures: Wearable sensor data, such as walking steps, conversation time, and sleep, were collected from August 2015 to October 2017, and positron emission tomography images were collected from October 2015 to December 2017. A multiple regression model and change-point regression model were used to examine the association of lifestyle factors with mean amyloid or fluorodeoxyglucose uptake, assessed on the basis of a standardized uptake value ratio of the frontal lobes, temporoparietal lobes, and posterior cingulate gyrus with the cerebellar cortex as the reference region. The bootstrap method was used to obtain nonparametric 95% CIs on the associations of lifestyle factors with cognitive decline. Results: Of the 855 adults in the study, 118 (13.8%) were diagnosed with mild cognitive impairment, with a mean (SD) age of 75.7 (5.8) years and 66 (55.9%) women. Total sleep time was inversely associated with fluorodeoxyglucose uptake after adjusting for covariates (ß = -0.287; 95% CI, -0.452 to -0.121, P < .001). Change-point regression showed an inverse association between total sleep time and mean amyloid uptake when sleep duration was longer than 325 minutes (B = -0.0018; 95% CI, -0.0031 to -0.0007). Conclusions and Relevance: To our knowledge, this is the first study to demonstrate that total sleep time was associated with brain function in older adults with mild cognitive impairment. Sleep duration is a potentially modifiable risk factor for dementia at the mild cognitive impairment stage.

Relationship Between the Japanese Version of the Montreal Cognitive Assessment and PET Imaging in Subjects with Mild Cognitive Impairment.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) test has high sensitivity and specificity for detecting mild cognitive impairment or early dementia. How the MoCA score relates to findings of positron emission tomography imaging, however, remains unclear. OBJECTIVE: This prospective study examined the relationship between the Japanese version of the MoCA (MoCA-J) test and brain amyloid deposition or cerebral glucose metabolism among subjects with mild cognitive impairment. METHODS: A total of 125 subjects with mild cognitive impairment underwent the MoCA-J test, and amyloid- and 18F-fluorodeoxyglucose- positron emission tomography. Linear correlation analysis and multiple linear regression analysis were conducted to investigate the relationship between the MoCA-J score and demographic characteristics, amyloid deposition, and cerebral glucose metabolism. Moreover, Statistical Parametric Mapping 8 was used for a voxel-wise regression analysis of the MoCA-J score and cerebral glucose metabolism. RESULTS: The MoCA-J score significantly correlated with age, years of education, and the Mini-Mental State Examination score. After adjusting for age, sex, and education, the MoCA-J score significantly correlated negatively with amyloid retention (ß= -0.174, p= 0.031) and positively with cerebral glucose metabolism (ß= 0.183, p= 0.044). Statistical Parametric Mapping showed that Japanese version of MoCA score correlated with glucose metabolism in the bilateral frontal and parietal lobes, and the left precuneus. CONCLUSION: The total MoCA-J score correlated with amyloid deposition and frontal and parietal glucose metabolism in subjects with mild cognitive impairment. Our findings support the usefulness of the MoCA-J test for screening subjects at high risk for Alzheimer's disease.

Modifiable Lifestyle Factors and Cognitive Function in Older People: A Cross-Sectional Observational Study.

Background: The development of evidence-based interventions for delaying or preventing cognitive impairment is an important challenge. Most previous studies using self-report questionnaires face problems with reliability and consistency due to recall bias or misclassification among older people. Therefore, objective measurement of lifestyle components is needed to confirm the relationships between lifestyle factors and cognitive function. Aims: The current study examined the relationship between lifestyle factors collected with wearable sensors and cognitive function among community-dwelling older people using machine learning. Methods: In total, 855 participants (mean age: 73.8 years) wore a wristband sensor for 7.8 days on average every 3 months. Various lifestyle parameters were measured, including walking steps, conversation time, total sleep time (TST), sleep efficiency, time awake after sleep onset, awakening count, napping time, and heart rate. Random forest (RF) regression analysis was used to examine the relationships between total daily sensing data and Mini-Mental State Examination (MMSE) scores. Confounding factor analysis was conducted with models that were adjusted and unadjusted for demographic and vascular risk factors, and selected variables were assessed as risk and protective factors using partial dependence plots (PDPs). Results: Lifestyle data were collected for 31.3 ± 7.1 days per year using wristband sensors. RF regression analysis adjusted for age, gender, and education levels selected four variables, including number of walking steps, conversation time, TST, and heart rate. Moreover, walking steps, conversation time, and heart rate remained after RF regression analysis adjusted for demographic and vascular risk factors. Number of walking steps, conversation time, and heart rate were categorized as protective factors, whereas TST was categorized as a risk factor for cognitive function. Although PDPs of number of walking steps and heart rate revealed continuously increased MMSE scores, those of conversation time and TST and revealed that the tendency in the graph was reversed at the boundary of a particular threshold (321.1 min for conversation time, 434.1 min for TST). Conclusions: Lifestyle factors, such as physical activity, sleep, and social activity appear to be associated with cognitive function among older people. Physical activity and appropriate durations of sleep and conversation are important for cognitive function.

Comparison of brain perfusion patterns in dementia with Lewy bodies patients with or without cingulate island sign.

AIM: The aim of the present study was to examine the differences in the brain perfusion single-photon emission computed tomography patterns compared in dementia with Lewy bodies (DLB) with or without cingulate island sign (CIS). METHODS: A total of 43 patients with DLB and 63 patients with Alzheimer's disease (AD) were included in the study. The CIScore was determined based on the posterior cingulate area and the occipital cortex using the eZIS software. The CIScore was analyzed using receiver operating characteristic curve analysis. Statistical parametric mapping 8 was used for the voxel-by-voxel group analysis of single-photon emission computed tomography. RESULTS: The mean CIScore was significantly lower in DLB patients than in Alzheimer's disease patients. The age at examination was higher in the normal CIScore subgroup than in the abnormal CIScore subgroup based on optimal cut-off value. Statistical parametric mapping 8 analysis showed Alzheimer's disease-specific hypoperfusion in the normal-CIScore subgroup. Furthermore, stratifying the patients by age before applying the optimal CIScore cut-off improved the largest area under the receiver operating characteristic curve in patients aged ≤78 years compared with patients aged >79 years. CONCLUSIONS: The present findings suggest that older DLB patients might have a normal CIScore because of concomitant multiple pathology. Therefore, age should be considered when interpreting the CIScore. Geriatr Gerontol Int 2019; 19: 197-202.

Effects of white matter lesions on brain perfusion in patients with mild cognitive impairment.

OBJECTIVE: To evaluate the effects of white matter lesions on regional cerebral blood flow in subjects with amnestic mild cognitive impairment. PATIENTS AND METHODS: Seventy-five subjects with mild cognitive impairment (36 men and 39 women; mean age, 78.1 years) were included in the study. We used the Mini-Mental State Examination to assess cognitive function. All subjects underwent brain magnetic resonance imaging and 99mTc ethylcysteinate dimer single photon emission computed tomography. Subjects were stratified based on the presence or absence of white matter lesions on magnetic resonance imaging. Statistical parametric mapping of differences in regional cerebral blood flow between the two groups were assessed by voxel-by-voxel group analysis using SPM8. RESULTS: Of all 75 subjects with mild cognitive impairment, 46 (61.3%) had mild to moderate white matter lesions. The prevalence of hypertension tended to be higher in subjects with white matter lesions than in those without white matter lesions. Mini-Mental State Examination scores were significantly lower in subjects with white matter lesions than in those without white matter lesions. Subjects with white matter lesions had decreased regional cerebral blood flow mainly in the frontal, parietal, and medial temporal lobes, as well as the putamen, compared to those without white matter lesions. CONCLUSION: In subjects with mild cognitive impairment, white matter lesions were associated with cognitive impairment and mainly frontal lobe brain function.

[A amyotrophic lateral sclerosis (ALS) 4 family misdiagnosed as hereditary spastic paraplegia-a case report].

We report a 44 years old man with slowly progressive muscular atrophy of the extremities for over 30 years. He experienced difficulty in walking in his 10's and was diagnosed as hereditary spastic paraplegia (HSP) in his 20's. And then, muscle atrophy of the extremities slowly progressed especially in his distal muscles. Sensory axonal neuropathy was detected with sural nerve biopsy. His father and uncle have been diagnosed as HSP in their early days. His father noticed weakness of his leg in his 20's. He lost motor function of the leg in his 60's. In addition, marked disturbance of thermal sensation, vibration, and sense of position were found by physical examination. Our genetic study detected senataxin (SETX) gene mutation (c.8C>T,p.T3I) in the blood of those two patients, and they had been identified as family cases of amyotrophic lateral sclerosis (ALS) 4. As clinical symptoms of ALS4 would be similar to those of HSP at the onset, we suggest considering ALS4 in seeing patients with HSP without gene diagnosis.

Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease.

AIM: The aim of the present study was to evaluate the relationship between baseline white matter lesions (WML) and changes in regional cerebral blood flow during longitudinal follow up of patients with Alzheimer's disease (AD). METHODS: A total of 38 patients with AD were included in the study (16 men, 22 women; mean age 77.8 years). All patients were evaluated using the Mini-Mental State Examination and brain perfusion single-photon emission computed tomography at baseline with an approximately 2-year follow up. The patients were divided into two subgroups according to the presence of WML on magnetic resonance imaging. Single-photon emission computed tomography data were analyzed using a voxel-by-voxel group analysis with Statistical Parametric Mapping 8 and region of interest analysis using FineSRT. Changes in Mini-Mental State Examination scores and regional cerebral blood flow were analyzed using the Wilcoxon signed-rank test. RESULTS: Mean Mini-Mental State Examination scores in AD patients with WML significantly decreased from 19.4 ± 4.8 to 15.5 ± 6.5 (P = 0.003). Statistical Parametric Mapping 8 and FineSRT analysis showed more severe and widespread regional cerebral blood flow reduction, mainly in the frontal and mesial temporal regions in AD patients with WML compared with those without WML. CONCLUSION: Baseline WML could predict a rapid progression of cognitive and brain functional impairment during longitudinal follow up in AD. Geriatr Gerontol Int 2016; 16: 836-842.

[A case of neurosarcoidosis with swelling and gadolinium enhancement of spinal nerve roots on magnetic resonance imaging].

An 80-year-old woman was admitted to our hospital because of developed sense of constriction in the trunk and gradually progressive numbness and muscle weakness in the upper and lower extremities. Cerebrospinal fluid analysis showed increased cell count and protein level. Gadolinium enhanced magnetic resonance imaging (MRI) of spine showed the enhancement and swelling of bilateral nerve root in the cervical and lumbar segments. Although chest computed tomography showed neither bilateral hilar lymphoadenopathy nor lung lesions and serum angiotensin converting enzyme and lysozyme (ACE) were normal, tuberculin skin test was negative and cell count and CD4/CD8 elevated in bronchoalveolar lavage fluid. Biopsy specimen of scalene lymph node showed noncaseating granuloma. The patient was treated with oral predonisolone, which improved her symptoms and abnormalities on MRI. It is important to consider neurosarcoidosis in the differential diagnosis of polyradiculopathy with swelling and gadolinium enhancement of spinal nerve roots.

[Case of Vogt-Koyanagi-Harada disease associated with non-herpetic acute limbic encephalitis with autoantibodies against glutamate receptor epsilon2 in the cerebrospinal fluid].

We report a case of Vogt-Koyanagi-Harada (VKH) disease associated with non-herpetic acute limbic encephalitis with autoantibodies against glutamate receptor epsilon2 in the cerebrospinal fluid. A 42-year-old woman developed a complaint of visual distortion, visual disturbance, headache and mild psychiatric symptoms, such as anxiety and depression. She was diagnosed as VKH through the fidings of fluorescein fundus angiography, which revealed patchy hypofluorescence associated with delayed choroidal filling at early fluorescein angiographic phase, and spotted choroidal hyperfluorescence and pooling of dye at late phase. Analysis of the cerebrospinal fluid (CSF) showed slight increase of leukocyte count (49/microl, mononuclear cells) and immunoglobulin (Ig) G index. An anti-GluRepsilon2 IgM antibody was positive in CSF. Brain magnetic resonance imaging (MRI) showed a monofocal hyperintensity lesion in the left parahippocampal gyrus on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. We diagnosed her VKH disease associated with non-herpetic acute limbic encephalitis. She was treated with oral prednisone, 70 mg day and her symptoms have gradually improved. To our knowledge, meningoencephalitis in VKH disease is extremely rare and the analysis of anti-GluRepsilon2 IgM antibody in CSF has not been reported. We speculate that a certain immunologic mechanism, including the anti-GluRepsilon2 IgM antibody, contributes to the pathogenesis of the VKH disease with non-herpetic acute limbic encephalitis.

Primary central nervous system lymphoma with cortical laminar hemorrhage.

Here we report a case of primary central nervous system (CNS) lymphoma with cortical laminar hemorrhage. The present case showed an acute onset of focal neurologic signs and bilateral cortical lesions surrounded by peripheral white matter edema on magnetic resonance imaging. A part of the left frontal cortical lesion was hyperintense on T1-weighted images and hypointense on T2-weighted and T2-weighted gradient-echo images, suggesting subacute laminar hemorrhage. The patient was initially diagnosed with multiple hemorrhagic infarctions, but a biopsy specimen revealed diffuse large B-cell lymphoma with hemosiderin deposits. Immunohistochemical studies revealed that the tumor cell cytoplasm and membrane stained positively for anti-vascular endothelial growth factor antibody. The present case reconfirms the danger of making a specific lymphoma diagnosis based on magnetic resonance imaging findings alone and that histopathologic examination following brain biopsy is necessary for a correct diagnosis. Vascular endothelial growth factor expression might be associated with the intratumoral hemorrhage.