Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese.

BACKGROUND: Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. METHODS: We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. RESULTS: In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%). CONCLUSIONS: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

An Extremely Delayed Onset of Frey Syndrome: A Case Report and Literature Review.

We report the case of an 80-year-old man with Frey syndrome that developed 30 years postoperatively, which is an exceptionally long period before its occurrence. Sweating and flushing occurred on only the side of his face where the surgery was performed, and he had no other causative abnormalities. Following treatment with botulinum toxin, the patient's symptoms resolved. Extremely early- and late-onset cases do not fit the conventional paradigm of this pathology. Various surgical methods to prevent this syndrome have been explored, but complete prevention has not yet been achieved. These findings suggest that the underlying pathophysiology of Frey's syndrome may be more complex than previously recognized.

Resveratrol Upregulates Senescence Marker Protein 30 by Activating AMPK/Sirt1-Foxo1 Signals and Attenuating H2O2-Induced Damage in FAO Rat Liver Cells.

Resveratrol (RSV) is a polyphenol with numerous biological functions, including anti-inflammatory, antioxidant, and anti-aging activities. The novel senescence marker protein-30 (SMP30) indicates aging, and it suppresses hepatic oxidative stress. However, the effects of RSV on SMP30 expression regulation remain unclear. We observed that RSV positively regulates SMP30 expression in rat hepatoma-derived FAO cells. However, this was abolished by Compound C and EX-527 that specifically inhibit AMP-activated protein kinase (AMPK) and Silent Information Regulator T1 (Sirt1), respectively. We predicted binding sites for AMPK, forkhead box protein O1 (Foxo1), and Sirt1 downstream molecules as possible SMP30 promoters using the JASPAR and UniProtKB databases. We identified a Foxo1 binding site in the promoter region of SMP30. Inhibiting Foxo1 with AS1842527 also decreased the RSV-induced upregulation of SMP30 expression. Moreover, RSV suppressed the substantial downregulation of SMP30 expression caused by oxidative stress and hydrogen peroxide (H2O2) and released accumulated lactate dehydrogenase. These results demonstrate that, as a novel food factor, RSV-induced upregulation of SMP30 by activating AMPK/Sirt1-Foxo1 signaling and may attenuates H2O2-induced oxidative damage. The findings of this study offer new perspectives of the anti-ageing properties of RSV.

Visualization of thrombus using iterative reconstruction and maximum intensity projection of thin-slice CT images.

OBJECTIVE: Iterative reconstruction (IR) is a noise reduction method that facilitates the synthesis of maximum intensity projection (MIP) from a larger number of slices while maintaining resolution. The present study aimed to analyze whether CT evaluation using IR and MIP is ideal for thrombus evaluation of large vessel occlusions in patients with acute ischemic stroke. METHODS: Three types of images for each patient were reconstructed and categorized into three groups: the "conventional group," evaluated using 0.5-mm slice CT, the "MIP group," evaluated using 0.5-mm slice CT processed with MIP, and the "IR + MIP group," evaluated with 0.5-mm slice CT processed with IR and MIP. Noise and image quality were evaluated with noise standard deviation (Noise SD) and contrast-to-noise ratio (CNR). Three experts evaluated the thrombus edge coordinates, made a visual assessment, and compared the data with the digital subtraction angiography (DSA) of the mechanical thrombectomy. RESULTS: Twenty-nine patients with cerebral infarction having large vessel occlusion were included in this study. The IR + MIP group had a lower Noise SD and a statistically higher CNR, leading to more favorable image evaluations. The thrombus assessment showed no inter-rater variability in thrombus edge identification, and the visual assessment and comparison with DSA were statistically better in the IR + MIP group. CONCLUSIONS: IR reduces noise and improves resolution. MIP in combination with IR facilitates visualization of thrombus.

Thyroid hormone decreasing after mechanical thrombectomy for cerebral infarction.

OBJECTIVE: Mechanical thrombectomy (MT) is an established treatment for large vessel occlusion in patients with cerebral infarction. The use of iodine contrast agent decreases thyroid hormone levels via the Wolff-Chaikoff effect. Low triiodothyronine (T3) syndrome caused due to severe illness status can contribute to decreased levels of thyroid hormones. Reportedly, a low T3 level is associated with poor prognosis in patients with cerebral infarction. This study aimed to clarify the changes in thyroid hormone levels in the acute phase after MT and the effects of the iodine contrast agent on these hormones. METHODS: This was a single-center, prospective, and single-arm trial. Thyroid stimulating hormone (TSH), free T3 (FT3), and free T4 (FT4) levels were tested on admission and 24 h postoperatively in patients who were approved for MT. RESULTS: A total of 37 patients were screened during the study period and 31 patients were enrolled in this study. Significant decreases were observed in TSH (P < 0.001) and FT3 (P < 0.001) levels 24 h after MT. Moreover, there was a correlation between the decrease in ratio of change in FT3 levels and the amount of iodine contrast agent used per body surface area (r = 0.43, P = 0.019), while no such correlations were detected for TSH and FT4. CONCLUSION: We demonstrated that TSH and FT3 levels decreased in the acute phase after MT and that FT3 levels were associated with the amount of iodine contrast agent used.

Scattered cerebral infarction in the corona radiata predicts worse outcomes.

OBJECTIVES: Intracranial branch atheromatous disease often results in progressive motor deficits in the lenticulostriate arteries (LSA). In some patients with LSA infarction, magnetic resonance imaging (MRI) revealed single lesions at the LSA origin from the middle cerebral artery spreading in a scattered manner toward the distal area. This study aimed to elucidate the clinical characteristics of such cases. MATERIALS AND METHODS: This was a single-center, retrospective study comprising 1,840 consecutive patients admitted to the Ina Central Hospital, Japan. Two neurologists selected patients with LSA infarctions on the basis of MRI data. Patients with a single mass of infarct lesion from the origin were classified as the single group, whereas patients with infarct lesions as a single mass at LSA origin but divided and independent as the infarct area extended distally were classified as the scattered group. We compared the clinical characteristics and outcomes in these groups. RESULTS: The single and scattered groups included 119 and 35 patients, respectively. We defined worsening as an increase of one point or more on the National Institute of Health Stroke Scale. Univariate analysis demonstrated that patients in the scattered group showed significantly more worsening after hospitalization compared with those in the single group (48.6% vs. 28.6%; p < .05). Moreover, this can easily lead to increased disease severity (p < .016). In a multivariate analysis, group (odds ratio, 2.5 [95% CI, 1.11-5.74], p < .03) was an independent predictor of symptom worsening. CONCLUSIONS: Scattered infarction in the corona radiata is an aggravating factor leading to worse outcomes.

Cavernous Sinus Swelling and Abducens Nerve Paresis Due to Intracranial Hypotension.

The most common neurological symptom of spontaneous intracranial hypotension (SIH) is abducens nerve paresis, and the precise pathophysiology is unclear. The accepted explanation is traction on the cranial nerves caused by the downward displacement of the cranial content. We herein report magnetic resonance imaging of SIH that can explain the mechanism underlying abducens nerve paresis. The cavernous sinuses were particularly thickened compared with the surrounding dura. This phenomenon can be explained by venous swelling, which can occur after leakage of cerebrospinal fluid in a closed cavity. This swelling pushes the abducens nerve up, which then causes abducens nerve paresis.

Persistent Working Memory Impairment Associated with Cerebral Infarction in the Anterior Cingulate Cortex: A Case Report and a Literature Review.

A 52-year-old man experienced sudden-onset global amnesia and left limb ataxia. An embolism of the right anterior cerebral artery resulted in anterior cingulate cortex (ACC) infarction, and working memory dysfunction persisted. The ACC, prefrontal cortex, and bilateral superior parietal lobule exhibited decreased activity on single-photon emission computed tomography (SPECT). The ACC handles working memory formation and is essential for the executive function. The areas showing a decreased activity on SPECT were responsible for the working memory, which corresponded to the observed symptoms. This is the first case in which limited ACC infarction resulted in permanent working memory dysfunction, and SPECT revealed the decreasing working memory in the associated region.

Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients.

Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.

A new threshold of apparent diffusion coefficient values in white matter after successful tissue plasminogen activator treatment for acute brain ischemia.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is effective for the treatment of acute brain ischemia, but may trigger fatal brain edema or hemorrhage if the brain ischemia results in a large infarct. Herein, we attempted to predict the extent of infarcts by determining the optimal threshold of ADC values on DWI that predictively distinguishes between infarct and reversible areas, and by reconstructing color-coded images based on this threshold. MATERIALS AND METHODS: The study subjects consisted of 36 patients with acute brain ischemia in whom MRA had confirmed reopening of the occluded arteries in a short time (mean: 99min) after tPA treatment. We measured the apparetnt diffusion coefficient (ADC) values in several small regions of interest over the white matter within high-intensity areas on the initial diffusion weighted image (DWI); then, by comparing the findings to the follow-up images, we obtained the optimal threshold of ADC values using receiver-operating characteristic analysis. RESULTS: The threshold obtained (583×10-6 m2/s) was lower than those previously reported; this threshold could distinguish between infarct and reversible areas with considerable accuracy (sensitivity: 0.87, specificity: 0.94). CONCLUSION: The threshold obtained and the reconstructed images were predictive of the final radiological result of tPA treatment, and this threshold may be helpful in determining the appropriate management of patients with acute brain ischemia.

Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study.

Spinocerebellar ataxia type 31 (SCA31) is known as a late-onset, relatively pure cerebellar form of ataxia, but a longitudinal prospective study on the natural history of SCA31 has not been done yet. In this prospective cohort study, we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan. Patients were evaluated every year for 4 years using the Scale for the Assessment and Rating of Ataxia (SARA) and the Barthel Index (BI). Of the 176 follow-up visits (91.5%), 161 were completed in this study. Five patients (11.4%) died during the follow-up period, and two patients (4.5%) were lost to follow-up. The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year (mean ± standard error). Shorter disease duration at baseline was associated with faster progression of the SARA score. Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years. Our prospective dataset provides important information for clinical trials of forthcoming disease-modifying therapies for cerebellar ataxia. It also represents a useful resource for SCA31 patients and their family members in genetic counseling sessions.

High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly.

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carpal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-5.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.

Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan.

Spinocerebellar ataxia type 31 (SCA31) is a recently defined subtype of autosomal dominant cerebellar ataxia (ADCA) characterized by adult-onset, pure cerebellar ataxia. The C/T substitution in the 5'-untranslated region of the puratrophin-1 gene (PLEKHG4) or a disease-specific haplotype within the 900-kb SCA31 critical region just upstream of PLEKHG4 has been used for the diagnosis of SCA31. Very recently, a disease-specific insertion containing penta-nucleotide (TGGAA)(n) repeats has been found in this critical region in SCA31 patients. SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for approximately 42% of ADCA families. We screened the insertion in 94 SCA31 patients from 71 families in Nagano. All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was inversely correlated with the age at onset but not associated with the progression rate after onset. (TAGAA)(n) repeats at the 5'-end of the insertion were variable in number, ranging from 0 (without TAGAA sequence) to 4. The number of (TAGAA)(n) repeats was inversely correlated to the total size of the insertion. The number of (TAGAA)(n) repeats was comparatively uniform within patients from the three endemic foci in Nagano. Only one patient, heterozygous for the C/T substitution in PLEKHG4, had the insertions in both alleles; they were approximately 3.0 and 4.3 kb in size. Sequencing and Southern hybridization using biotin-labeled (TGGAA)(5) probe strongly indicated that the 3.0-kb insertion, but not the 4.3-kb insertion, contained (TGGAA)(n) stretch. We also found that 3 of 405 control individuals (0.7%) had the insertions from 1.0 to 3.5 kb in length. They were negative for the C/T substitution in PLEKHG4, and neither of the insertions contained (TGGAA)(n) stretch at their 5'-end by sequencing. The insertions in normal controls were clearly detected by Southern hybridization using (TAAAA)(5) probe, while they were not labeled with (TGGAA)(5) or (TAGAA)(5) probe. These data indicate that control alleles very rarely have a nonpathogenic large insertion in the SCA31 critical region and that not only the presence of the insertion but also its size is not sufficient evidence for a disease-causing allele. We approve of the view that (TGGAA)(n) repeats in the insertion are indeed related to the pathogenesis of SCA31, but it remains undetermined whether a large insertion lacking (TGGAA)(n) is nonpathogenic.

Cerebral hemorrhage in Fabry's disease.

Fabry's disease is an X-linked lysosomal storage disorder resulting from alpha-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabry's disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabry's disease who developed cerebral hemorrhage. One patient had classic type Fabry's disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabry's disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients.

Severity and progression rate of cerebellar ataxia in 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA) in the endemic Nagano Area of Japan.

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.

A -16C>T substitution in the 5' UTR of the puratrophin-1 gene is prevalent in autosomal dominant cerebellar ataxia in Nagano.

The molecular bases of autosomal dominant cerebellar ataxia (ADCA) have been increasingly elucidated, but 17-50% of ADCA families still remain genetically undefined in Japan. In this study we investigated 67 genetically undefined ADCA families from the Nagano prefecture, and found that 63 patients from 51 families possessed the -16C>T change in the puratrophin-1 gene, which was recently found to be pathogenic for 16q22-linked ADCA. Most patients shared a common haplotype around the puratrophin-1 gene. All patients with the -16C>T change had pure cerebellar ataxia with middle-aged or later onset. Only one patient in a large, -16C>T positive family did not have this change, but still shared a narrowed haplotype with, and was clinically indistinguishable from, the other affected family members. In Nagano, 16q22-linked ADCA appears to be much more prevalent than either SCA6 or dentatorubral-pallidoluysian atrophy (DRPLA), and may explain the high frequency of spinocerebellar ataxia.

Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families.

The frequency of autosomal-dominant cerebellar ataxia (ADCA) subtypes was examined in 86 unrelated families originating from Nagano prefecture. In Nagano, the prevalence of spinocerebellar degeneration (SCD) was approximately 22 per 100,000 population. Among ADCA families, SCA6 was the most prevalent subtype (16 families, 19%), followed by DRPLA (nine families, 10%), SCA3/MJD (three families, 3%), SCA1 (two families, 2%), and SCA2 (one family, 1%). No families with SCA7, SCA12, or SCA17 were detected. Compared with other districts in Japan, the prevalence of SCA3/MJD was very low in Nagano. More interestingly, the ratio of genetically undetermined ADCA families was much higher in Nagano (55 families, 65%) than in other districts in Japan. These families tended to accumulate in geographically restricted areas such as Kiso, Saku, and Ina, indicating that the founder effect might be responsible for the high frequency of ADCA in these areas. Most patients clinically showed slowly progressive pure cerebellar ataxia of late-onset (ADCA III). In the case of 36 patients from 36 genetically undetermined ADCA III families, however, no one was completely consistent with the founder allele proposed for 16q-ADCA. These results indicate that there might be genetically distinct ADCA subtypes in Nagano.