Alzheimer's disease (AD), a chronic neurodegenerative disorder characterized clinically by progressive loss of cognitive and behavioral function, is the most common form of dementia in the world.2) The underlying pathogenesis of AD is caused by neuronal loss related to the abnormal extracellular accumulation of amyloid-beta peptide in oligomeric form and in neuritic plaques, as well as the intraneuronal aggregation of hyperphosphorylated tau in the form of neurofibrillary tangles.3) There are several other factors that contribute to neuronal degeneration, including inflammation, oxidative stress, and glutamatergic dysfunction.The pathogenesis of AD is multifactorial. It has been proposed that inappropriate activation of N-methyl-D-aspartate (NMDA) receptors is responsible for part of the neuronal toxicity and cognitive impairment observed in AD. 4,5) Abnormalities in glutamatergic signaling associated with AD have been linked to excitotoxicity caused by the excessive influx of Ca through the NMDA receptor calcium channel during sustained low-level stimulation of glutamatergic neurons. 6)Cumulative evidence indicates that glutamate-related alteration in AD can be corrected to some extent by NMDA receptor antagonists such as memantine. [7][8][9] In humans, it is known that brain monoamine oxidase (MAO)-B activity is higher in AD and normal aging whereas it is lower in psychiatric disorders such as depression, cycloidal psychosis, etc. [10][11][12] In psychiatric patients, it is also known that brain MAO-B activity is correlated with platelet MAO activity. 10,13) The increase in brain MAO-B is most likely due to transcriptional elevation of MAO-B protein 14) and predominant in plaque-associated astrocytes in neuropathologically verified AD brains.15,16) MAO-B inhibitors such as selegiline and rasagiline are effective in some central nervous system disorders such as AD and Parkinson's disease by oxidative stress.17) The two types of MAO (EC.1.4.3.4), MAO-A and MAO-B, exhibit differences in sensitivity towards their selective inhibitors as well as in their amino acid sequences. [18][19][20][21] MAOs play an important role in the inactivation of monoamine neurotransmitters in the central and peripheral nervous systems. MAO-A metabolizes serotonin (5-HT, 5-hydroxytryptamine) and noradrenaline while MAO-B metabolizes benzylamine and b-phenylethylamine. Tyramine and dopamine (DA) are metabolized by both MAO-A and MAO-B. MAO-A is selectively and irreversibly inhibited by clorgyline, and selegiline is known to be a selective and irreversible inhibitor of MAO-B. Conversely, moclobemide is a selective but reversible MAO-A inhibitor whereas lazabemide is a selective and reversible MAO-B inhibitor. 22,23) We reported earlier that amantadine enhanced the inhibition of reuptake of both 5-HT and DA, weakly inhibits MAO activity in mice brain, and that 5-HT induced the headtwitch response (HTR).24) The numbers of HTR induced by 5-HT in mice is an effective method to evaluate serotonergic effects of drugs in vivo.25) It has been ge...
The issue of whether serum lipid marker values are cognitively and neurologically significant for elderly individuals attending a memory clinic has been controversial. We investigated the associations of serum lipid markers with the memory function and cortical structure in 52 patients aged ≥75 years who had attended our memory clinic based on their subjective memory complaints. None had a history of medication for hyperlipidemia. The Wechsler Memory Scale-Revised (WMS-R) was administered to all patients for the assessment of their memory function. Serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDLC), and triglyceride (TG) were measured for each patient. Surface-based morphometry (SBM) was performed for the calculation of each patient's cortical thickness and gyrification index based on structural MRI data. Our analyses revealed that the serum HDLC level was positively and significantly correlated with the WMS-R subtests of visual paired associates I/II and logical memory I (p < 0.05). The serum TG level was negatively correlated with the logical memory I subtest. The SBM results showed positive correlations between the serum HDLC level and the gyrification indices of the bilateral insular and frontal opercular cortices, and those two gyrification indices were positively correlated with the logical memory I and visual paired associates I/II. These results suggest that in these elderly patients, a high serum HDLC level was associated with not only preserved memory function but also gyrification of the insular and frontal opercular cortex. We conclude that elderly individuals' serum lipid markers should be carefully assessed in memory clinic settings, because serum HDLC may be a biomarker for memory function and cortical structure.
We investigated whether a self-rated anosognosia score can be an indicator for progression of brain atrophy in patients with amyotrophic lateral sclerosis (ALS). Scores for 16 patients were compared with the ventricular areas of the bilateral anterior and inferior horns measured on x-ray computed tomography. Longitudinal enlargement was expressed as a monthly increase in size: (ventricular size at the initial scan – ventricular size at the follow-up scan)/scan interval (months). The anosognosia scores ranged from –4 to 3 and 3–18 in patients with and without frontotemporal lobar degeneration (FTLD), respectively (p = 0.0011). Anosognosia scores were significantly correlated with sizes of anterior (r = 0.704, p = 0.0016) and inferior (r = 0.898, p < 0.0001) horns. In non-demented patients for whom follow-up CT scans were available (n = 7), the scores were significantly correlated with the longitudinal increase in inferior horn size (r = 0.754, p = 0.0496), but not with that of anterior horn size (r = –0.166, p = 0.7111). In conclusion, anosognosia in ALS is associated with greater anterior and inferior horn sizes, reflecting frontotemporal lobar atrophy. Moreover, mild anosognosia in ALS patients without FTLD may predict impending inferior horn enlargement, reflecting medial temporal atrophy.
Cerebrospinal fluid (CSF) shunts are frequently used to treat hydrocephalus. The use of a programmable shunt valve allows physicians to easily change the opening pressure. Since patients with adjustable CSF shunt valves may use portable game machines, the permanent magnets in these machines may alter the shunt valve programmed settings or permanently damage the device. This study investigated the risk of unintentional valve adjustment associated with the use of game machines in patients with programmable CSF shunt valves. Four adjustable valves from 4 different manufacturers, Sophysa Polaris model SPV (Polaris valve), Miethke proGAV (proGAV), Codman Hakim programmable valve (CHPV), and Strata II small valve (Strata valve), were evaluated. Magnetic field interactions were determined using the portable game machine, Nintendo DS Lite (DS). The maximum distance between the valve and the DS that affected the valve pressure setting was measured by x-ray cinematography. The Polaris valve and proGAV were immune to unintentional reprogramming by the DS. However, the settings of the CHPV and Strata valves were randomly altered by the DS. Patients with an implanted shunt valve should be made aware of the risks posed by the magnetic fields associated with portable game machines and commonly used home electronics.
There are many reports on grapefruit juice (GFJ) increasing the apparent oral bioavailability of several clinically important drugs metabolized by the most abundant isoform of cytochrome P450, i. e. CYP 3A4. Azelnidipine (Calblock (R)) is a long-lasting 1, 4-dihydropyridine calcium antagonist currently used in the treatment of hypertension in Japan. In a drug interaction study using human liver microsomes, several CYP3A4 inhibitors and substrates inhibited the oxidative metabolism of azelnidipine to the same extent as nifedipine and felodipine. In order to evaluate the possible interaction of azelnidipine with GFJ in humans , a randomized, two-way crossover study was conducted in eight Japanese healthy volunteers.A single oral dose of 8mg azelnidipine was administered orally with either 250mL water or GFJ after overnight fasting. Blood samples were drawn periodically up to 24hours after dosing. Plasma concentrations of azelnidipine were measured by liquid chromatography-tandem mass spectrometry (LC/APCI-MS/MS).Concomitant administration of azelnidipine with GFJ increased the mean C. of azelnidipine by 2.5-fold and the AUC by 3.3-fold compared with water; moreover, the time to reach Cmax (tmax) and the mean residence time (MRT) were slightly delayed. No serious adverse events were observed except one subject described mild symptoms of drug-related headache and flushing accompanied with orthostatic hypotension at 4hrs after administration in the GFJ phase. The results demonstrated the pharmacokinetic interaction between azelnidipine and a single glass of GFJ.
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