Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment.

Vitamin B12 deficiency is associated with cognitive impairment, hyperhomocysteinemia, and hippocampal atrophy. However, the recovery of cognition with vitamin B12 supplementation remains controversial. Of the 1716 patients who visited our outpatient clinic for dementia, 83 had vitamin B12 deficiency. Among these, 39 patients (mean age, 80.1 ± 8.2 years) had undergone Mini-Mental State Examination (MMSE) and laboratory tests for vitamin B12, homocysteine (Hcy), and folic acid levels. The hippocampal volume was estimated using the z-score of the MRI-voxel-based specific regional analysis system for Alzheimer's disease. This is multi-center, open-label, single-arm study. All the 39 patients were administered vitamin B12 and underwent reassessment to measure the retested for MMSE and Hcy after 21−133 days (median = 56 days, interquartile range (IQR) = 43−79 days). After vitamin B12 supplementation, the mean MMSE score improved significantly from 20.5 ± 6.4 to 22.9 ± 5.5 (p < 0.001). Hcy level decreased significantly from 22.9 ± 16.9 nmol/mL to 11.5 ± 3.9 nmol/mL (p < 0.001). Significant correlation was detected between the extent of change in MMSE scores and baseline Hcy values. The degree of MMSE score was not correlated with hippocampal atrophy assessed by the z-score. While several other factors should be considered, vitamin B12 supplementation resulted in improved cognitive function, at least in the short term, in patients with vitamin B12 deficiency.

Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment.

Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.

Rho-kinase ROCK inhibitors reduce oligomeric tau protein.

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3ß or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3ß, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

Subventricular glial nodules in neurofibromatosis 1 with craniofacial dysmorphism and occipital meningoencephalocele.

BACKGROUND: Neurofibromatosis 1 (NF1) is autosomally inherited disorder, characterized by café au lait spots and multiple neurofibromas. Subventricular glial nodules (SVGN) are multiple gliosis bulging into the ventricular lumen, and histologically consist of astrocytes and their processes. Damage to ependymal cells induces SVGN formation. CASE REPORT: This case report describes a 50-year-old man with NF1, craniofacial dysmorphism, including sphenoid dysplasia, bone defects at the middle posterior fossa, with disconnection of the parieto-occipital sutures, and the left orbital bone, and occipital meningoencephalocele. He died of status epileptics. Pathologically, many SVGN were found around the ventricular wall. Many ependymal cells were stripped during ventricular dilatation. Therefore, to prevent brain tissue insult from direct exposure to CSF, the proliferation of astrocytes and their processes was speculated to have substitute for ependymal cells and induced SVGN formation.

Acute Prevertebral Abscesses Caused by Bacterial-infected Traumatic Tooth Fractures.

We report a case of acute prevertebral abscess caused by traumatic tooth fractures in a 77-year-old Japanese man. After being transferred to our hospital the patient was initially diagnosed with a neck hematoma; however, blood culture showed Streptococcus parasanguinis, an oral bacterium, and an MRI examination suggested prevertebral abscesses. Tooth fractures, severe periodontitis, and peri-implantitis with Streptococcus parasanguinis were observed. Antibiotics were administered and fractured teeth were extracted. The patient's condition then gradually improved. We concluded that bacteremia caused by traumatic tooth fractures induced the acute prevertebral abscesses.

[A case of various illusion, and hallucination caused by occipital lobe infarction].

A 70-year-old right-handed man noticed that the right side of the screen on his television displayed a time lag compared to the other side. For five days before admission, he had characteristic polyopia, visual photopia, and complex hallucination. Upon neurological examination, he showed no abnormal findings except for right homonymous hemianopia. MRI showed acute infarction of the occipital gyri and part of the lingual gyrus in the left occipital lobe. After admission, he experienced various visual hallucinations and visual illusions, including metamorphopsia and micropia, many times. They gradually disappeared after 2 months. Various hallucination was caused by the release of visual information, and illusion was thought to be due to integration failure of visual information. The appearance of complex hallucination in the blind visual field is known due to the damage of the region on the left occipital gyrus. However, the cases with various symptoms such as visual photopia and micropsia are rare.

[Guillain-Barré syndrome associated with acute hepatitis A-A case report and literature review].

A 44-year-old female developed acute hepatitis A (HA) 5 weeks after ingesting raw oysters. She developed ascending motor weakness, bilateral peripheral facial nerve palsy, and bulbar symptoms. A diagnosis of demyelinating Guillain-Barré syndrome (GBS) was made on the basis of her clinical manifestations and the results of a nerve conduction study. The patient showed improvement following combination treatment with intravascular immunoglobulin and high dose methylprednisolone. No antibodies against specific gangliosides, sulfated glucuronyl paragloboside (SGPG), or sulfatide were detected. HA virus (HAV) RNA was isolated from her serum and its full-length genome sequence was determined. It revealed a homology of 99.9% or more with HAV genotype IA (HAV-IA) of the 2014 outbreak. No mutant virus RNA was detected.

[Reversible cerebral vasoconstriction syndrome: a clinical study of 11 cases].

This study reports eleven cases of reversible cerebral vasospasm syndrome (RCVS). Of the 11 patients, two were males and nine were females, with the average age of 47.9 ± 14.1 years. Many of these patients were young. The rates of severe, intractable and pulsative headache, generalized convulsions, and motor hemiparesis were 64%, 27%, and 36%, respectively. As complications of intracerebral lesions in the early stage of disease onset, convexal subarachnoid hemorrhage, lobar intracerebral hemorrhage, and posterior reversible encephalopathy syndrome were observed in 63%, 9%, and 45% of cases, respectively. Cerebral infarction occurred in 45% of cases at around 1-3 weeks after onset. Improvement of cerebral vasoconstriction was recognized in several cases from about the first month of onset. The post-partum period, migraine, transfusion, rapid amelioration for anemia, renal failure, bathing, and cerebrovascular dissection were suspected as disease triggers. Abnormally high blood pressure at onset was confirmed in 55% of cases. It is important to analyze the pathophysiology of RCVS associated with these triggers from the viewpoint of the breakdown of the blood-brain barrier.

[Guillain-Barré syndrome following cytomegalovirus infection with increased level of antibody against moesin-a case report].

A 28-year-old man noticed sensory disturbance in the distal parts of his four extremities and muscle weakness of his hands two weeks after cytomegalovirus (CMV) infection. He had splenomegaly, impairment of hepatic function and peripheral neuropathy with decreased tendon reflexes. Protein-cell dissociation was observed in the cerebrospinal fluid, and the nerve conduction study (NCS) showed the changes due to demyelination. Intravenous immunoglobulin therapy was performed for 5 days after the diagnosis of Guillain-Barré syndrome. He did not show any severe symptoms such as bulbar palsy and was discharged on day 16. Anti-GM2 and anti-GalNAc-GD1a IgM antibodies were detected and acute inflammatory demyelinating polyneuropathy following the CMV infection was confirmed. NCS showed the abnormal changes were normalized after 4 months. The levels of antibodies against moesin, which is a protein existing in trace amounts in node of Ranvier, were increased. However, the antibodies were not detected 4 months after therapy. These changes were well correlated to his clinical course.

[Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with heterozygote mutation of GJB1 gene: case report of a female patient].

A 32-year-old woman showed transient central type facial nerve palsy and bulbar symptoms. Brain MRI revealed high intensity signals in the cerebral white matter, splenium of corpus callosum, and posterior limb of internal capsule. Two elder brothers of the patient had distal dominant peripheral neuropathies in four limbs. In this family, the point mutation of GJB1 gene, encoding connexin 32, was revealed and X-linked Charcot-Marie-Tooth disease (CMTX1) was diagnosed. The presented case was a heterozygote of this mutation. She showed severe transient central nervous system (CNS) symptoms and subclinical demyelinating peripheral neuropathy. The CNS symptoms and alterations of brain images were very similar among three siblings. There are many reports on male patients with CMTX1 who show associated CN symptoms, but female patients are very rare. There has been no previous report of a CMTX1 patient similar to the patient presented here. The trigger factors have been recognized at the onset of transient CN symptoms in these cases. The prevention of these factors is important for the management of such patients.

[CADASIL with cysteine-sparing NOTCH3 mutation manifesting as dissociated progression between cognitive impairment and brain image findings in 3 years: A case report].

A 55-year-old man with no history of stroke or migraine presented to the clinic with cognitive impairment and depression that had been experiencing for two years. Neurological examination showed bilateral pyramidal signs, and impairments in cognition and attention. Brain MRI revealed multiple lacunar lesions and microbleeds in the deep cerebral white matter, subcortical regions, and brainstem, as well as diffuse white matter hyperintensities without anterior temporal pole involvement. Cerebral single-photon emission computed tomography (SPECT) revealed bilateral hypoperfusion in the basal ganglia. Gene analysis revealed an arginine-to-proline missense mutation in the NOTCH3 gene at codon 75. The patient was administered lomerizine (10 mg/day), but the patient's cognitive impairment and cerebral atrophy continued to worsen. Follow-up testing with MRI three years after his initial diagnosis revealed similar lacunar infarctions, cerebral microbleeds, and diffuse white matter hyperintensities to those observed three years earlier. However, MRI scans revealed signs of increased cerebral blood flow. Together, these findings suggest that the patient's cognitive impairments may have been caused by pathogenesis in the cerebral cortex.

[Rapidly deteriorated lobar intracerebral hemorrhages: possible association of varicella zoster virus-vasculopathy].

A 75-year-old man having dementia and lifestyle related diseases developed a lobar intracerebral hemorrhage (LICH) in the left parietal and a small cerebellar infarction in the left occipital lobe. Many micro bleeds (MB) due to cerebral amyloid angiopathy (CAA) in the subcortical areas and multiple vascular stenosis were also found by MRI and MRA. He developed herpes zoster in his buttocks on day 6 of hospitalization and complicated with varicella zoster virus (VZV) meningitis with positive for VZV-DNA in the cerebrospinal fluid. Subsequently, LICHs occurred in the left frontal lobe and in the right parietal lobe for a short period of time and died on the day 18. We speculated that the repeating hemorrhages was primarily caused by VZV vasculopathy and additionally the subcortical MBs increased the hemorrhagic risk. The relationship between VZV vasculopathy and CAA should be studied in the future.

Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization.

Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer's disease (AD) and vascular dementia. However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that consist of pathologically phosphorylated tau proteins. The effect of homocysteine (Hcy) on tau aggregation was explored using human neuroblastoma M1C cells that constitutively express human wild-type tau (4R0N) under the control of a tetracycline off system, primary mouse cultured neurons, and by inducing hyperhomocysteinemia in a mouse model of tauopathy (HHCy mice). A wide range of Hcy concentrations (10-1000 µM) increased total tau and phosphorylated tau protein levels. Hcy activated glycogen synthase kinase 3, and cyclin dependent kinase 5, major tau phosphokinases, and inactivated protein phosphatase 2A, a main tau phosphatase. Hcy exhibited cytotoxic effects associated with enhanced activation of caspase. Truncation of tau in the C-terminus, the cleavage site of caspase 3 (i.e., D421, detected by the TauC3 antibody) was also increased. Total tau, phosphorylated tau, as well as C-terminal cleaved tau were increased in the sarkosyl insoluble tau fraction. Hcy also increased the level of tau oligomers, as indicated by the tau oligomer complex 1 (TOC1) antibody that specifically identifies oligomeric tau species, in the tris insoluble, sarkosyl soluble fraction. The levels of TOC1-positive oligomeric tau were increased in brain lysates from HHCy mice, and treating HHCy mice with S-adenosylmethionine, an intermediate of Hcy, reduced the levels of oligomeric tau to control levels. These observations suggest that Hcy increases the levels of phosphorylated tau as well as truncated tau species via caspase 3 activation, and enhanced tau oligomerization and aggregation.

[Trigeminal Herpes Zoster Presenting with High-intensity Signals for the Spinal Trigeminal Nucleus and Tract on Diffusion-weighted Image: A Case Report of Stroke Mimic].

A 50-year-old woman was admitted to our hospital with dysesthesia on the right upper portion of her face and a headache. Diffusion-weighted brain magnetic resonance imaging (MRI) revealed high-intensity signals in the dorsolateral portion of the medulla oblongata. She was diagnosed with lateral medullary infarction and was intravenously treated with sodium ozagrel. On the second day of hospitalization, she had nausea and vomiting and showed nystagmus to all directions, suggesting damage to the vestibular nucleus. These manifestations coincided with partial symptoms of lateral medullary syndrome. On the third day of hospitalization, a rash appeared on the region of skin innervated by the first and second branches of the right trigeminal nerve. A reevaluation of the MRI findings indicated the presence of a lesion of the right spinal trigeminal nucleus and tract. She was treated with acyclovir for 14 days, and was discharged without any residual symptoms. Varicella zoster virus-DNA was detected in her cerebrospinal fluid. This disease mimics the presentation of a stroke and is important for differential diagnosis. (Received August 1, 2017; Accepted September 14, 2017; Published February 1, 2018).

[Clinical, epidemiological, and etiological studies of adult aseptic meningitis: a report of 12 cases of herpes simplex meningitis, and a comparison with cases of herpes simplex encephalitis].

We treated 437 cases of adult aseptic meningitis and 12 cases (including 2 recurrent patients; age, 31.8 ± 8.9 years; 7 females) of herpes simplex meningitis from 2004 to 2016. The incidence rate of adult herpes simplex meningitis in the cases with aseptic meningitis was 2.7%. One patient was admitted during treatment of genital herpes, but no association was observed between genital herpes and herpes simplex meningitis in the other cases. The diagnoses were confirmed in all cases as the cerebrospinal fluid (CSF) was positive for herpes simplex virus (HSV)-DNA. For diagnosis confirmation, the DNA test was useful after 2-7 days following initial disease onset. Among other types of aseptic meningitis, the patients with herpes simplex meningitis showed relatively high white blood cell counts and relatively high CSF protein and high CSF cell counts. CSF cells showed mononuclear cell dominance from the initial stage of the disease. During same period, we also experienced 12 cases of herpes simplex encephalitis and 21 cases of non-hepatic acute limbic encephalitis. Notably, the patients with herpes simplex meningitis were younger and their CSF protein and cells counts were higher than those of the patients with herpes simplex encephalitis.

Influenza A (H3N2)-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging.

BACKGROUND: Rhabdomyolysis with influenza infection is rarely reported in adults. We report here influenza A induced rhabdomyolysis and anterior compartment syndrome (ACS). CASE REPORT: This case report describes a 43-year-old woman exhibiting influenza A induced rhabdomyolysis. High levels of creatine kinase (97,000 IU/L) and high titer of anti-influenza A virus antibody (H3N2) (320 ×) with negative anti-influenza B virus antibody were observed. T2 fat suppression muscle MRI imaging showed high-intensity signals in rectus femoris, vastus lateralis, adductor magnus, and semimembranosus (SM) muscles. The existence of ACS was suspected out. Muscle biopsy showed that fiber size variations exist without infiltration of inflammatory cells. The symptoms and muscle MRI findings of T2 fat suppression imaging was markedly improved. CONCLUSIONS: Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain.

[A case of optic perineuritis-A literature review of Japanese cases and clinical problems].

A 64-year-old woman was admitted to our hospital owing to decreased visual acuity and visual field defect. She had a similar history of decreased visual acuity and received steroid therapy 10 years ago. Brain MRI revealed gadolinium-enhancement in the sheath of the optic nerve, called "tram-track" and "doughnut" signs. Optic perineuritis (OPN) was diagnosed on the basis of her clinical manifestations, which improved on treatment with high-dose methylprednisolone (mPSL). However, clinical manifestations relapsed 10 days post-discharge; hence, she was re-admitted. She was re-administered high-dose mPSL and subsequent oral administration of prednisolone. She had no relapse or recurrence for the last 2 years. We reviewed studies involving Japanese patients with OPN, including 17 idiopathic and 14 secondary cases and found that 43% of patients had recurrences and 30% of patients had poor outcome including severe residuals of visual acuity. Secondary OPN occurred owing to various diseases manifesting generalized systematic inflammation. Timely and suitable treatment was very important for clinical favorable outcomes in OPN.

Serum 1,5-Anhydroglucitol: Risk Factor of Acute Ischemic Stroke and Transient Ischemic Attack in Well-Controlled Diabetes.

BACKGROUND: Serum 1,5-anhydroglucitol (1,5-AG) levels are a measure that provides information on daily glycemic variations. We evaluated whether 1,5-AG could be a possible marker of acute ischemic stroke (AIS) or transient ischemic attacks (TIA) in patients with diabetes mellitus (DM). METHODS: We retrospectively reviewed electronic medical records of 5,294 AIS/TIA patients. Of the 5,294, 1,898 had diabetes and in 1,246, serum 1,5-AG levels were measured (group S). Group S was divided into 2 subgroups: hemoglobin A1c (HbA1c) <7% (S-low) and >7% (S-high). As controls, 394 outpatients with diabetes (group C) without AIS/TIA were likewise divided into subgroups, C-low and C-high according to HbA1c level. In each HbA1c subgroup, the association between serum 1,5-AG (≥14 vs. <14 µg/mL) and stroke was examined using multivariable logistic regression (MLR) with stepwise variable selection. In model 1, the OR and 95% CI was examined adjusted for age and gender. Known risk factors for stroke; hypertension, dyslipidemia, alcohol consumption, smoking, and estimated glomerular filtration rate were included in model 2. RESULTS: Overall, serum 1,5-AG levels were lower in group S than in group C. Serum 1,5-AG levels were low in subgroups S-high and C-high, showing no differences in mean values. However, mean serum 1,5-AG levels in S-low was statistically lower than that in C-low. MLR analysis showed that the OR for low (<14 µg/mL) 1,5-AG for stroke was statistically significant only in well-controlled diabetes (OR [95% CI] 2.19 [1.54-3.10]) in model 1 and (2.26 [1.56-3.28]) model 2. CONCLUSIONS: Low serum 1,5-AG levels could be a possible marker for AIS/TIA risk in patients with well-controlled DM.

Retraction:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: A case presented brain calcification and corpus callosum atrophy from over 10 years before the onset of dementia.

This article was retracted by author's request.