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A 19-year-old man with a history of Chiari type I malformation was admitted to our hospital two times within a 2-month period because of bacterial meningitis. Cerebrospinal fluid (CSF) analysis showed neutrophilic pleocytosis and hypoglycorrhachia. During the second admission, we became aware of hearing loss on the right since age 15 years. High-resolution temporal bone CT showed soft tissue opacification of the right epitympanum and external auditory canal. Tissue biopsy resulted in CSF otorrhea and pneumocephalus. CT cisternography revealed a temporal bone CSF leak. Brain MRI showed a dural defect localized to the anterior petrous apex. Using a combined middle cranial fossa-transmastoid approach, the dural defect and associated arachnoid granulations were located along the superior side of the greater petrosal nerve and repaired. A CSF leak without underlying pathology, such as trauma, surgery, or congenital abnormality, is defined as spontaneous. Spontaneous CSF leak should be considered as a cause of recurrent bacterial meningitis even when CSF otorrhea and fluid behind the tympanic membrane are clinically absent.

Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.

Recently, Alzheimer's disease (AD) is understood as "diabetes of the brain" or "type 3 diabetes." Recent clinical trials of anti-amyloid β-protein (Aβ) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aβ degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aβ-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.

The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = −0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

Recently, Alzheimer’s disease (AD) is understood as “diabetes of the brain” or “type 3 diabetes.” Recent clinical trials of anti-amyloid β-protein (Aβ) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aβ degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aβ-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.

Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.

Objective: Intracellular amyloid b-protein (Ab) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. Methods: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APPKM670/671NL/ PS1M146V) and a tau gene mutation (TauP301L). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Ab degradation, activity of Ab-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. Results: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Ab, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Ab, increased activity of proteasome and insulin-degrading enzyme, protected against H2O2 toxicity, and decreased p53 protein levels in the cultured cells. Interpretation: 3xTg-AD mice show intraneuronal Ab accumulation and memory disturbances before extracellular Ab deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Ab and p-tau levels by APO treatment strongly suggest that intraneuronal Ab is an important therapeutic target and APO will be a novel drug for AD. ANN NEUROL 2011;69:248–256

A healthy 60-year-old female presented with acute-onset low back pain, fever, reduced consciousness, and meningeal irritation. Gram-positive cocci were observed in the cerebrospinal fluid, and methicillin-susceptible Staphylococcus aureus was cultured from blood and cerebrospinal fluid. Spinal magnetic resonance imaging demonstrated osteomyelitis around L5 (Fig. A). This article is protected by copyright. All rights reserved.

detected by immunoprecipitation and double-labeling immunofluorescence. Results: As oligomer, PrP c, Fyn, NMDA receptor, GSK3s, and phosphorylated tau were detected in lipid rafts of doubleTg mice. As oligomer-PrP c complex accumulated in lipid rafts. According with As oligomer accumulation, fyn, phosphorylated NMDA receptor, phosphorylated tau, and GSK3s increased in lipid rafts of double Tg mice compared to that of single tau Tg mice. Conclusions: These findings suggest that As oligomer-PrP c complex may induce Fyn, and phosphorylation of both NMDA receptor and tau in lipid rafts leading to neurodegeneration.

We report a case of mononeuropathy multiplex with idiopathic thrombocytopenic purpura (ITP). A 78-year-old man developed patches of purpura on his left forearm. His platelet count was 11,000/microl and platelet-associated IgG was elevated. He was diagnosed as having ITP. At the beginning of the following month, he noticed dysesthesia and weakness of his left finger and left lower limb, as well as dysesthesia of his bilateral lower thighs. Neurological examination revealed weakness in the area of the left ulnar nerve and of the left anterior tibial muscle. Dysesthesia presented in the area of the left ulnar nerve and bilateral superficial peroneal nerves. Nerve conduction studies revealed asymmetric axonal sensorimotor neuropathy (mononeuropathy multiplex). A cerebrospinal fluid specimen showed a normal cell count and normal protein level Serum anti-ganglioside antibody was negative. The platelet count gradually increased after the introduction of corticosteroid therapy. His neurological deficits and electrophysiological findings also improved. Immune-mediated neuropathy was suggested as the cause of his mononeuropathy multiplex with ITP.

Erectile dysfunction, dysuria, photophobia, and chronic cough developed insidiously in a 49-year-old man from his third decade. Severe difficulty of urination resulted in intermittent catheterization. He had six family members who had suffered similar autonomic symptoms with or without motor deficits. He presented asymmetrical tonic pupils, a neurogenic bladder, and mild sensory impairment in the distal parts of the bilateral lower limbs without orthostatic hypotension and motor deficits. Nerve conduction studies revealed mild axonal changes with slightly reduced conduction velocities in the lower limbs. His left pupil over-responded to instillation with 0.125% pilocarpine. Functional bladder tests showed an atonic bladder, suggesting postganglionic parasympathetic involvement. Autonomic evaluation for sympathetic components including head-up tilt, beat to beat responses to Valsalva's maneuver, cardiac MIBG imaging, plasma catecholamine levels and sweat tests were all normal. A genetic test disclosed a heterozygous mutation of myelin protein zero (MPZ); p.Thr124Met. Selectively distributed dysautonomia in this pedigree may indicate parasympathetic postganglionic components including the ganglion as the primary target of this mutated MPZ in the autonomic nervous system.

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder, characterized by the accumulation of iron in regions such as the basal ganglia. We enrolled 28 patients with childhood intellectual disability and young-onset parkinsonism (≤40 years at onset) and 4 patients with infantile neuroaxonal dystrophy. All had been clinically diagnosed, and the prevalence of genetic mutations linked to NBIA ( PANK2 [exons 1–7], PLA2G6 [exons 2–17], C19orf12 [exons 1–3], WDR45 [exons 2–11], COASY [exons 1–9], FA2H [exons 1–7], and RAB39B [exons 1, 2]) was evaluated. We detected 7 female patients (25.0%, 7 of 28) with de novo heterozygote WDR45 mutations, which are known to be pathogenic for beta-propeller protein-associated neurodegeneration. All 7 patients had common clinical features. Pathogenic mutations in other NBIA genes were not found. We also screened 98 patients with early-onset parkinsonism without intellectual disability and 110 normal controls of Japanese origin for WDR45 mutations. None had WDR45 mutations. Our data suggest a high frequency of beta-propeller protein-associated neurodegeneration mutations in the Japanese population.