Makoto Hamamoto

Long-Term Estrogen Replacement Therapy in Female Patients with Dementia of the Alzheimer Type: 7 Case Reports

Seven female patients with mild to moderate dementia of the Alzheimer type (DAT) were treated with long-term, low-dose estrogen replacement therapy (ERT) over a period of 5-45 months. Five of the 7 patients were cases who had responded well to short-term ERT with 1.25 mg/day of conjugated equine estrogens (CEE) for 6 weeks. The 7 patients from 56 to 77 years of age received 0.625 mg/day of CEE for 21 days, followed by a pause of 7 days. A 28-day cycle of low-dose ERT was performed repeatedly. In 4 cases, these patients received 5 mg/day of medroxyprogesterone acetate (MPA) during the last 10-12 days of estrogen treatment. Therapeutic efficacy of estrogen was evaluated by psychometric assessments such as the Mini-Mental State Examination (MMSE) and the Hasegawa Dementia Scale (HDS) and a behavior rating scale of the Gottfries-Bråne-Steen geriatric rating scale (GBS). The MMSE and HDS evaluations were performed principally once in 2-4 weeks. In 4 out of the 7 patients, the MMSE and HDS scores were elevated above the pretreatment levels during ERT. The termination of ERT resulted in a decrease in both scores. Furthermore, the GBS scores and daily activities of the same 4 patients were improved during ERT. In these 4 patients cognitive functions were markedly improved throughout the treatment period, while the other 2 patients responded moderately well and another patient did not respond at all. These observations suggest that long-term, low-dose ERT improves cognitive functions, dementia symptoms and daily activities in women with mild to moderate DAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Function of sigma1 receptors in Parkinson's disease

Objective –  The objective of this study was to investigate the mapping of sigma1 receptors in Parkinsons disease (PD) using [11C]SA4503 and positron emission tomography (PET), and to assess whether sigma1 receptors are involved in the damaged dopaminergic system in PD patients.

Adenosine A2A Receptors Measured with [11C]TMSX PET in the Striata of Parkinson's Disease Patients

Adenosine A2A receptors (A2ARs) are thought to interact negatively with the dopamine D2 receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinsons disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.

Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group

A large scale multicenter study of cerebrospinal fluid (CSF) tau levels was conducted to determine the cut-off value, sensitivity and specificity for clinical usage as a biomarker of Alzheimers disease (AD). Its use for early and differential diagnosis and the factors that increase CSF tau levels were also examined. CSF samples from a total of 1,031 subjects including 366 patients with AD, 168 patients with non-Alzheimer type dementia (NA), 316 patients with non-dementia neurological diseases (ND) and 181 normal controls (NC) were measured using ELISA for tau. The cut-off value of tau, 375 pg/ml, showed 59.1% sensitivity and 89.5% specificity for diagnosis of AD compared with the other groups. The tau levels were increased from the early to late stages of AD. Elevation of CSF tau in the non-tauopathy and tauopathy dementia groups, chronic and acute damage to the cerebrum, and meningeal disturbance were other factors that required attention for clinical practice. Measurement of CSF tau was useful as a biomarker for early and differential diagnosis of AD.

The effect of ascorbic acid on the pharmacokinetics of levodopa in elderly patients with Parkinson disease

Levodopa (LD) is one of the most effective drugs for clinical symptoms in patients with Parkinson disease (PD). Most PD patients are advanced in age and may have trouble with LD absorption because aging influences drug absorption processes. Previous reports have indicated that ascorbic acid (AsA) can reduce LD dosage without losing its effectiveness. The current study sought to determine whether AsA affects LD absorption in elderly PD patients. Sixty-seven elderly PD patients took a tablet orally containing 100 mg LD and 10 mg carbidopa following an overnight fast. Plasma LD concentrations were determined at 6 points up to 3 hours, using high-performance liquid chromatography with electrochemical detection. The area under the curve (AUC), peak drug concentration (Cmax), and time to peak drug concentration (Tmax) were calculated. The pharmacokinetic evaluation was repeatedly performed 1 week later in the same way except for adding 200 mg AsA to the tablet. The changes in AUC, Cmax, and Tmax between the tests were evaluated. Significant changes in these parameters were not observed when analyzed using data from all patients. However, significant increases in AUC and Cmax, and a significant reduction in Tmax by adding AsA were observed in 25 patients with baseline AUC ≤2500 ng·hour/mL. In conclusion, AsA can improve LD absorption in elderly PD patients with poor LD bioavailability. LD therapy in combination with AsA may be one of the strategies for PD treatment.

Influence of ageing on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease

Levodopa (LD) is the most effective drug to treat the symptoms of Parkinsons disease (PD). It has been reported that the bioavailability of LD is higher in elderly patients than in young patients; however, it is not known how ageing changes the bioavailability of LD among elderly patients. In this study, we compared the pharmacokinetics of LD between two groups of elderly PD patients, early- (75 years or younger) and late-elderly (76 years or older). After oral administration of a tablet containing 100 mg LD per 10 mg carbidopa in 155 PD patients, we measured plasma LD concentrations. Peak drug concentration (C(max)), time to peak drug concentration (T(max)), halftime of drug (T1/2) and area under the curve (AUC) were determined. AUC and T1/2 were significantly higher and longer, respectively, in the late-elderly group than in the early-elderly group (p < 0.05 and <0.05, respectively). However, C(max) and T(max) were not statistically different between the groups. The present data indicate that LD absorption is consistent in PD patients, regardless of age. The difference in oral LD bioavailability between the groups may result from a difference in excretion ability. Physicians should consider LD pharmacokinetics when treating elderly PD patients.

Factors influencing outcome in Guillain–Barré Syndrome: comparison of plasma adsorption against other treatments

OBJECTIVE This study was performed to evaluate which factors influence the outcome of Guillain-Barré Syndrome (GBS), focusing on the choice of treatments. METHODS Sixty-three GBS patients were retrospectively studied and the following factors were evaluated: sex, age, days from onset of disease to the start of treatment, severity of symptoms, prior infection, autonomic dysfunction, bulbar palsy, anti-ganglioside antibody, and disease form, as well as the choice of treatment. Plasma adsorption (PA, n=39), plasma exchange (PE, n=14), or immunoglobulin treatment (IVIg, n=10) were performed in this study. Outcomes were evaluated using the functional grading scale (FGS) of Hughes. RESULTS The number of days needed for one functional grade improvement was significantly longer in the elderly, the severe symptom group, and patients with acute motor axonal form, and days needed for two functional grade improvement was significantly longer in the elderly, patients with autonomic dysfunction, and acute motor axonal form. The choice of treatments (PA, PE, or IVIg) did not significantly influence the outcome as determined by both univariate and multivariate analysis. CONCLUSION Although patient age, symptoms, and disease form influenced the outcome, treatment methods did not significantly influence the outcome. Since PA does not result in a risk of unknown infection, choosing a PA treatment may be justified, especially for patients (or doctors) who may be anxious about a possibility of unknown infection.

Initial Symptoms of Parkinson’s Disease with Elderly Onset

Background/Objective: As the incidence of Parkinson’s disease (PD) is related to aging, we consider it important to determine how the initial symptoms change with age in order to diagnose early elderly cases of PD accurately. Methods: 84 patients (age at onset 70.7 ± 9.0 years; mean ± 1 SD) were studied to see whether the initial symptoms change according to age. Results: The prevalence of resting tremor was significantly lower in patients of advanced age (p = 0.041). In contrast, the incidence of postural and gait disorders increased significantly with aging (p = 0.032). The prevalences of rigidity and kinetic disorders, which are important clinical features of PD, were not influenced by aging. Conclusion: These findings suggest that the cause of PD is not related to the aging process itself, since the prevalences of all symptoms were not influenced by aging. Knowledge of the prevalence of the inital symptoms of PD may contribute to the accurate diagnosis in early and elderly cases.

Neuromyelitis optica preceded by brain demyelinating episode.

Neuromyelitis optica (NMO) is considered a distinct disease from multiple sclerosis (MS) because of its pathogenesis. It is well accepted that NMO selectively affects the spinal cord and optic nerve and is not associated with brain lesions at the onset of the disease, unlike MS. We present a unique case where the patients initial lesion was in the brain, and optic neuritis and myelitis were revealed 6 years after the brain lesion. In addition, the patients serum antiaquaporin 4 (AQP4) antibody was positive. We consider the brain lesion to precede abnormal lesion of NMO, and the AQP4 measurement is important for diagnostics, even if it occurs with brain lesions.

Short-term plasticity of central benzodiazepine receptors in status epilepticus: case report

123I‐iomazenil SPECT is of value in determining an epileptogenic focus, however, transient uptake change has been rarely reported in epileptic disorders. A 78‐year‐old woman diagnosed as status epilepticus (SE) showed transient reduction in 123I‐iomazenil uptake within the epileptic foci on SPECT images during a couple of weeks. It suggests a seizure‐related ‘short‐term’ plasticity in the central benzodiazepine receptors and dynamic change in the regulatory mechanisms of inhibitory neurotransmitter system within the epileptic foci in patients with SE.