Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid ß Diffusion.

The relationship between oral health and the development of Alzheimer's disease (AD) in the elderly is not yet well understood. In this regard, the association between aging or neurodegeneration of the trigeminal nervous system and the accumulation of amyloid-ß(1-42) (Aß42) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aß42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aß42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and AppNL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aß42 oligomer processing in the Vmes, which exhibits high amyloid-ß (Aß) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aß42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aß, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aß in AppNL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aß42 oligomers with the formation of Aß42 oligomer clusters in AppNL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aß42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aß42 oligomers in AppNL-G-F mice. These results suggest that autophagy maintains homeostasis in Vmes neurons and that deterioration of autophagy due to aging or neurodegeneration leads to the diffusion of Aß42 oligomers into the extracellular space and possibly the development of AD.

Creatinine to Cystatin C Ratio as a Marker of Bone Property in Older Adults: The J-SHIPP Study.

OBJECTIVES: To clarify whether serum creatinine to cystatin C ratio (CCR), a marker of muscle mass and muscle function may be used as a simple marker of bone property. DESIGN: A cross-sectional analysis. SETTING: A general population-based observation study. PARTICIPANTS: 1,606 middle-aged to elderly (≥50 years, mean age: 66.9 ± 7.5 years old) men (n = 642) and post-menopausal women (n = 964). MEASUREMENT: Speed of sound (SOS) at the calcaneal bone was used as a surrogate marker of bone mineral density. The cross-sectional area of the muscle at the mid-thigh was measured using computed tomography. RESULTS: There was significant linear correlation between the quartiles of CCR and SOS (Q1: 1,495 ± 25, Q2: 1,499 ± 24, Q3: 1,507 ± 26, Q4: 1,511 ± 25 m/sec; P < 0.001) even in a sex-separated analysis. This association was independent of major covariates (Q1: ß = -0.126, P < 0.001; Q2: ß = -0.096, P = 0.001; Q3: ß = -0.022; P = 0.412, Q4: reference) and the mid-thigh muscle mass, while creatinine alone or eGFR did not show clear association with SOS. CONCLUSION: The CCR may be used as a simple marker of bone property independently of muscle mass in a general population with preserved renal function.

Auraptene in the Peels of Citrus Kawachiensis (Kawachibankan) Contributes to the Preservation of Cognitive Function: A Randomized, Placebo-Controlled, Double-Blind Study in Healthy Volunteers.

OBJECTIVES: Dementia, which is characterized by a progressive decline in cognitive function, is a major concern in aging societies. Although a number of treatments have been approved, an effective therapy to prevent the disorder is lacking. A supplement that improves cognitive function would benefit patients. The aim of this study was to assess whether auraptene, a citrus coumarin, has a protective effect on cognitive decline. DESIGN: A randomized, placebo-controlled, double-blind study SETTING: Outpatient medical check-up program for cognitive disorders PARTICIPANTS: 84 adult volunteers (they are cognitively normal) met inclusion and exclusion criteria to participate. INTERVENTION: 42 participants received auraptene enriched (containing 6.0 mg/day of auraptene) test juice, and another participants received placebo juice. MEASUREMENTS: 1) Mild Cognitive Impairment (MCI) Screen using the 10-word immediate recall test. 2) The Mini-Mental State Examination (MMSE). Cognitive assessment ware carried out baseline and at 24 weeks. RESULTS: Auraptene enriched test juice did not improve cognitive function after 24 weeks compared with baseline data. However, there was a significant difference in the percentage change in cognitive function between the test and placebo orange juice groups (6.3 ± 18.9 vs. -2.4 ± 14.8, P < 0.05). Multiple regression analysis demonstrated a significant independent relationship between the percentage change in the 10-word immediate recall test score and test juice consumption including baseline 10-word immediate recall test score in all subjects. CONCLUSION: This is the first study to assess the effectiveness of auraptene in the prevention of cognitive decline. Our results suggest that auraptene is a safe supplement for the prevention of cognitive decline.

CSF angiotensin II and angiotensin-converting enzyme levels in anti-aquaporin-4 autoimmunity.

BACKGROUND: Anti-aquaporin-4 (AQP4) antibody targets perivascular astrocyte foot processes, which contain abundant angiotensinogen, a precursor of angiotensin II, angiotensin-converting enzyme (ACE) and ACE2. OBJECTIVE: To disclose any abnormality in the intrathecal angiotensin II metabolic pathway in Japanese patients with neuromyelitis optica (NMO) or NMO spectrum disorders (NMOs) and positive for anti-AQP4 antibody. METHODS: We measured CSF angiotensin II, ACE and ACE2 levels in 15 anti-AQP4 antibody-positive patients with NMO or NMOs, 21 anti-AQP4 antibody-negative multiple sclerosis (MS) patients, 32 patients with other neurological diseases (OND) and 24 non-neurologic controls, using established ELISAs. RESULTS: CSF angiotensin II levels were lower in patients with NMO/NMOs (2.01+/-1.82 pg/ml) and those with MS (3.15+/-1.67 pg/ml) than in the OND (5.41+/-2.34 pg/ml) and control groups (6.71+/-2.65 pg/ml) (P(corr)<0.005). The difference in CSF angiotensin II levels between NMO/NMOs and MS patients was nearly significant (P(uncorr)=0.052). In NMO/NMOs and MS patients, angiotensin II levels were negatively correlated with CSF/serum albumin ratio (P<0.05). ACE levels in CSF were lower in patients with NMO/NMOs (34.3+/-5.61 ng/ml) than in MS patients (42.5+/-8.19 ng/ml, P(corr)=0.035) and controls (44.7+/-4.02 ng/ml, P(corr)<0.0003) while ACE2 levels were lower in NMO/NMOs (1.13+/-0.49 ng/ml) and MS (1.75+/-0.86 ng/ml) patients than in controls (2.76+/-0.23 ng/ml, P(corr)<0.001 for both). CONCLUSION: CSF angiotensin II, ACE, and ACE2 levels are decreased in NMO/NMOs patients with anti-AQP4 antibody, reflecting severe destruction of perivascular astrocytes.

Phenotypic spectrum of hereditary neuralgic amyotrophy caused by the SEPT9 R88W mutation.

BACKGROUND: Hereditary neuralgic amyotrophy (HNA), also known as hereditary brachial plexus neuropathy, has phenotypic and genetic heterogeneity. Mutations in the septin 9 (SEPT9) gene were recently identified in some HNA patients. The phenotypic spectrum of HNA caused by SEPT9 mutations is not well known. OBJECTIVE: To characterise the phenotype of a large family of HNA patients with the SEPT9 R88W mutation. METHODS: We report clinical, electrophysiological, neuroimaging and genetic findings of six HNA patients from a Japanese family. RESULTS: All 17 neuropathic episodes identified were selectively and asymmetrically distributed in the upper-limb nerves. Severe pain was an initial symptom in 16 episodes (94%). Motor weakness occurred in 15 (88%) and sensory signs in 10 (59%). A minor dysmorphism, hypotelorism, was seen in all. Nerve conduction studies revealed focal demyelination as well as prominent axonal degeneration changes. Needle electromyography revealed chronic neurogenic patterns only in the upper limbs. An MRI study showed a gadolinium-enhanced brachial plexus. The missense mutation c.262C>T; p.R88W was found in exon 2 of SEPT9 in all patients. CONCLUSIONS: The SEPT9 R88W mutation in this family causes selective involvement of the brachial plexus and upper-limb nerves. Wider and more universal recognition of clinical hallmarks and genetic counselling are of diagnostic importance for HNA caused by the SEPT9 mutation.

Extensive vasogenic edema of anti-aquaporin-4 antibody-related brain lesions.

OBJECTIVE: Using neuroimaging, we analyzed the nature of extensive brain lesions in five anti-aquaporin-4 (AQP4) antibody-positive patients with neuromyelitis optica spectrum disorders. RESULTS: Extensive brain lesions involved white matter in three, and basal ganglia and corpus callosum in one each. Four patients showed high diffusivity on apparent diffusion coefficient maps and three demonstrated increased choline/creatine ratios and decreased N-acetyl-aspartate/creatine ratios on (1)H-magnetic resonance spectroscopy. These findings suggested that the lesions were vasogenic edema associated with inflammation. Unusual brain symptoms associated with such lesions included recurrent limbic encephalitis, parkinsonism, and coma. CONCLUSION: Anti-AQP4 antibody is considered to be associated with the neuroimaging appearances of vasogenic edema.

Simultaneous measurement of arterial transit time, arterial blood volume, and cerebral blood flow using arterial spin-labeling in patients with Alzheimer disease.

BACKGROUND AND PURPOSE: Cerebral hemodynamics abnormality in Alzheimer disease (AD) is not fully understood. Our aim was to determine whether regional hypoperfusion due to AD is associated with abnormalities in regional arterial blood volume (rABV) and regional arterial transit time (rATT) as measured by quantitative arterial spin-labeling (ASL) with multiple-delay time sampling. MATERIALS AND METHODS: Nineteen patients with AD (9 men and 10 women; mean age, 74.5 +/- 8.6 years) and 22 cognitively healthy control subjects (11 men and 11 women; mean age, 72.8 +/- 6.8 years) were studied by using a quantitative ASL method with multiple-delay time sampling. From the ASL data, maps of regional cerebral blood flow (rCBF), rABV, and rATT were generated. A region of hypoperfusion due to AD was determined by statistical parametric mapping (SPM) analysis. Mean rCBF, rABV, and rATT values within the hypoperfused region were compared between the AD and control groups. RESULTS: Despite the significantly lower rCBF (P = .0004) in patients with AD (27.8 +/- 7.1 mL/100 g/min) in comparison with control subjects (36.7 +/- 6.3 mL/100 g/min), no significant difference in rATT was observed between the control (0.48 +/- 0.09 seconds) and AD (0.47 +/- 0.10 seconds) groups. Mean rABV was lower in the AD group (0.22 +/- 0.10%) than in the control group (0.27 +/- 0.12%), though the difference did not reach the level of statistical significance. CONCLUSIONS: Our results revealed that regional hypoperfusion in AD is not associated with rATT prolongation, suggesting that the mechanism of hypoperfusion is distinct from that in cerebrovascular diseases.

Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis.

BACKGROUND: We reported a reduction in the levels of angiotensin II in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS). OBJECTIVE AND METHODS: To clarify the mechanism underlying this reduction, we assayed angiotensin-converting enzyme (ACE) and ACE2 concentrations along with angiotensin II concentrations in CSF samples from 20 patients with MS and 17 controls with non-neurological diseases. RESULTS: ACE levels were significantly elevated in patients with MS compared with controls (48.42 +/- 4.84 vs 44.71 +/- 3.9 pg/mL), whereas ACE2 levels were significantly reduced (2.56 +/- 0.26 vs 2.78 +/- 0.24 pg/mL), acting toward a normalization of angiotensin II levels. CONCLUSION: These results further indicate an alteration of the intrathecal renin-angiotensin system in patients with MS.

Reduced angiotensin II levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

BACKGROUND: Recent studies suggest that angiotensin II, a major substrate in the renin-angiotensin system, protects neurons through stimulation of its type 2 receptors. However, quite a few clinical studies of angiotensin II levels have shown their relation to disease severity in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). AIMS OF THE STUDY: To clarify the significance of angiotensin II in ALS. METHODS: We assayed angiotensin II concentrations in cerebrospinal fluid (CSF) samples from 23 patients with ALS, nine patients with spinocerebellar degeneration (SCD) and 24 control individuals. We evaluated the disability levels of patients with ALS using the Revised ALS Functional Rating Scale (ALSFRS-R) and calculated the disease progression rate (DPR). RESULTS: CSF angiotensin II levels were significantly lower in the ALS group compared with that in the control group (P = 0.00864), and showed a significant positive correlation with scores on the ALSFRS-R, and a significant negative correlation with the DPR. CONCLUSIONS: In the present study, we reveal for the first time that angiotensin II levels in the CSF from patients with ALS are significantly reduced and significantly associated with disease severity and progression rate. These findings suggest that reduced levels of intrathecal angiotensin II may play a role in ALS.

Increase of CD4+TNF{alpha}+IL-2-T cells in cerebrospinal fluid of multiple sclerosis patients.

Intracellular production of TNFalpha and IL-2 after stimulation with phorbol myristate/ionomycin was flowcytometrically measured in CD4(+) T cells from peripheral blood (PB) and cerebrospinal fluid (CSF) of 29 patients with multiple sclerosis (MS), and 16 with other inflammatory and 41 with other non-inflammatory neurological diseases. In CSF, the percentages of CD4(+)TNFalpha(+)IL-2(-)T cells were significantly higher in patients with MS than either of the controls, whereas no difference was found in CD4(+)TNFalpha(+)IL-2(+)T or CD4(+)TNFalpha(-)IL-2(+)T cells. The increase was more pronounced at relapse than in remission. No significant change was detected in PB. These findings suggested that CD4(+)TNFalpha(+)IL-2(-)T cells are intrathecally upregulated in MS.

Intracellular amyloid beta-protein as a therapeutic target for treating Alzheimer's disease.

The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimer's disease (AD). On the basis of this hypothesis, inhibition of amyloid beta-protein (Abeta) generation and aggregation, enhancement of extracellular Abeta removal, and Abeta vaccination are currently under investigation. Intracellular Abeta may be even more important than extracellular Abeta, since intraneuronal Abeta accumulation commonly precedes extracellular Abeta deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Abeta such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic Abeta42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, Abeta-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular Abeta42. Therefore, intraneuronal Abeta represents an alternative therapeutic target. While inhibition of Abeta production and anti-Abeta immunotherapies are likely to attenuate both intraneuronal and extracellular Abeta toxicity, more specific anti-intraneuronal Abeta therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular Abeta and advocate intracellular Abeta as an important therapeutic target in AD.

Association of the HLA-DRB1 alleles with characteristic MRI features of Asian multiple sclerosis.

BACKGROUND: In Asian patients with multiple sclerosis (MS), a paucity of brain lesions and longitudinally extensive spinal cord lesions (LESCLs) extending three or more vertebral segments are characteristic findings on magnetic resonance imaging (MRI). We aimed to disclose possible factors contributing to the development of such MRI features. METHOD: Genotyping of HLA-DRB1 and -DPB1 alleles was performed in 121 consecutive Japanese patients with clinically definite MS based on the Poser criteria and 125 healthy controls. Possible factors associated with MRI features were determined by multiple logistic analysis. Patients with MS were classified based on the presence or absence of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) and LESCLs. Barkhof brain lesion-negative (-) patients had a markedly lower frequency of HLA-DRB1*0901 than controls (P(corr) < 0.05), whereas the frequency of DRB1*1501 was increased in the Barkhof brain lesion-positive (+) group, although this increase was not significant after correction. No Barkhof(-)LESCL(+) patients carried DRB1*0901 (P(corr) < 0.05), despite this being the most common allele in Japanese. The Barkhof(-)LESCL(-) group showed a significant increase in the frequency of DRB1*0405 compared with controls (P(corr) < 0.05). None of the DPB1 alleles were significantly different among the groups. Using multiple logistic analysis, the absence of oligoclonal bands was positively associated with an absence of Barkhof brain lesions, whereas a higher EDSS score was positively associated with the presence of LESCLs; however, the presence of anti-aquaporin-4 antibodies was not associated with either feature. CONCLUSION: The characteristic MRI features in Asians are partly related to distinct HLA-DRB1 gene alleles and an absence of oligoclonal bands.

Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16.

We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.

The contactin 4 gene locus at 3p26 is a candidate gene of SCA16.

OBJECTIVE: To identify of the gene responsible for the onset of spinocerebellar ataxia type 16 (SCA16). METHODS: We reanalyzed the linkage of the original Japanese pedigree using updated information, including three additional subjects. We then screened all exons located in the critical region. RESULTS: We reassigned the locus of SCA16 to 3p26.2-pter (maximum logarithm-of-odds score = 5.177) and identified only one point mutation (4,256C-->T) in the 3' untranslated region of the contactin 4 gene (CNTN4) on chromosome 3p26.2-26.3, which cosegregated with the disease. This mutation was not detected in 520 control subjects; moreover, we revised the phenotype of SCA16 from pure to complicated SCA. CONCLUSION: The contactin 4 gene (CNTN4) is associated with cerebellar degeneration in spinocerebellar ataxia type 16. Additional studies are necessary to prove 4,256C-->T to be a causative mutation.

History of allergic disorders in common neurologic diseases in Japanese patients.

OBJECTIVE: To clarify the association between past and present history of allergic disorders and neurologic diseases. METHODS: The past and present history of common allergic disorders together with family history was prospectively studied in all out-patients at the Department of Neurology at Kyushu University Hospital from March 1998 to February 2000. RESULTS: Among 3113 out-patients, 2152 (69.1%) completed a questionnaire. Myelitis showed a statistically significant increase of concomitant atopic dermatitis (P=0.006) and concomitant and past atopic dermatitis (P=0.014), as compared with neurologically healthy controls. Moreover, patients with lower motoneuron disease (LMND) had a statistically significant increase of past and concomitant asthma (P=0.007). None of the other common neurologic diseases showed any increase of allergic disorders when compared with controls. CONCLUSIONS: The present study supports the significant association between allergic disorders and such spinal cord diseases as myelitis and LMND in Japanese patients.

Adult-onset hereditary sensory and autonomic neuropathy accompanied by anosmia but without skin ulceration.

We report a novel type of hereditary sensory and autonomic neuropathy (HSAN) with adult onset in a Japanese family. One male and 2 females of 6 siblings were affected. They developed anosmia initially at the ages of 20-50 years, followed by anhidrosis and sensory loss. Skin ulceration was absent. Both superficial and deep sensation were impaired in the most distal parts of all 4 limbs. Orthostatic hypotension was present in all patients. This is a unique subtype of HSAN distinct from the HSAN I-V described by Dyck.