Konosuke Iwamoto

Serological Profiles of Urate, Paraoxonase-1, Ferritin and Lipid in Parkinson’s Disease: Changes Linked to Disease Progression

Background: Oxidative stress plays a role in the pathogenesis of neuronal death. Serum levels of urate or lipid were associated with the incidence of Parkinson’s disease (PD). Objective: We compared urate, paraoxonase-1 (PON1), iron, ferritin and lipid in sera of 119 PD patients and 120 healthy controls matched by age, sex and body mass index. We aimed to elucidate whether those serological data are correlated with disease progression. Results: Mean age (SD) of PD patients was 73.4 (8.7) years. Mean Yahr stage (SD) was 3.2 (0.9). Mean disease duration (SD) was 6.9 (5.1) years. Mean dose of L-DOPA (SD) was 355 (157) mg/day. As compared to controls, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), urate and PON1 activity were significantly reduced, and serum ferritin levels were significantly increased in male and female PD patients. Serum urate levels and PON1 activities were inversely related, and serum ferritin levels were correlated with Yahr stage and PD duration in men and women. Serum levels of TC and LDL-C were inversely related to Yahr stage or PD duration in female patients. Conclusions: Our studies indicated serological profiles of urate, PON1, ferritin, TC and LDL-C in PD patients. These serological changes were linked to PD progression. Metabolism of lipid, oxidant- and antioxidant-related substances may contribute to the pathogenesis and the progression of PD.

Beneficial effect of pramipexole for motor function and depression in Parkinson's disease.

We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson’s disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson’s Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.

Pulse Wave Velocity Study in Middle-Aged Migraineurs at Low Cardiovascular Disease Risk

(Headache 2011;51:1239‐1244)

Atorvastatin treatment attenuates motor neuron degeneration in wobbler mice.

We aimed to study whether atorvastatin treatment can retard motor neuron degeneration in wobbler mice. Wobbler mice and their normal littermates were fed 0.01% atorvastatin-mixed food (10 mg/kg/day) or regular food from age 3–4 weeks of disease onset for four weeks (n=10/group) or more than eight weeks (n=10/group). Motor function was evaluated by pull-strength and deformity scale of the forelimbs. For those symptomatic assessment and body weight were measured weekly. Neuropathological and biochemical changes of the biceps muscle and the cervical cord were analyzed at four weeks after treatment. Compared to vehicle, atorvastatin-treated wobbler mice delayed progression of forelimb motor deficits by more than four weeks. Wobbler mice significantly increased body weight from three weeks post-treatment of atorvastatin, compared with vehicle (p<0.05). Atorvastatin administration suppressed denervation atrophy at 30% (p<0.01), maintained choline acetyl transferase activities of the biceps muscle (p<0.05), and attenuated approximately 30% loss of motor neurons in wobbler mice (p<0.01). Atorvastatin fed to normal littermates did not influence body weight gain, neuropathological and biochemical findings. These data suggest that atorvastatin has neuroprotective effects on denervating muscles and degenerating motor neurons in wobbler mice.

Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer’s disease receiving donepezil

Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-D-aspartate receptor antagonist, memantine, in patients with Alzheimer’s disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10–22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3–14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.

Depression in multiple sclerosis.

With interest we read the excellent article by Lobentanz et al. concerning a large number of multiple sclerosis (MS) patients in relation to disability, depressive mood and quality of life (QOL) (1). They reported MS patients had significantly lower QOL than healthy controls. Expanded disability states scale (EDSS) (2) and self-rating depressive scale (SDS) (3) predicted global QOL. They finally concluded that depressive mood is the main factor influencing QOL. Depression is common in MS patients and contributes to cognitive dysfunction. Diagnosing depression in MS patients and initiating appropriate treatment is important. We studied 48 patients with MS to elucidate the nature and frequency of the depressive state by comparing group of MS patients against ageand education-matched controls. We also examined the relationship between severity of the illness and the depressive state. Patients completed the SDS and underwent a complete neurological evaluation and were asked to rate their state of neurological well-being on a scale of 1 (poor) to 5 (normal). Neurological disability was measured using EDSS. Correlations between SDS score, self-rating scale and EDSS were performed. The mean SDS score was higher in the MS patients than those of the controls and there was no correlation between SDS score and EDSS. Furthermore, no relationship between SDS and duration of disease was observed. However, there was a correlation between SDS score and a self-rating assessment. A self-assessment rating scale may provide a valuable ascertaining of depression in MS patients. For psychological well-being it is important to MS patients that doctors should pay attention to mental care and medical treatment. In addition, improving the depression condition provides adequate treatment choice to MS patients. In our limited experience concerning the relationship between neurological disability and the depressive state in amyotrophic lateral sclerosis, upper motor neuron sign was correlated with depressive state (Y. Iwaski, unpublished data). Further studies are needed to clarify the relationship between neurological symptoms and signs, and the depressive state in MS patients.

Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset

BackgroundThere have been several reports concerning the survival time after symptom onset in patients with amyotrophic lateral sclerosis (ALS). However, little is known about how the choice of physician (i.e., general practitioner, neurologist, etc.) may affect the time it takes for a diagnosis of ALS to be made.MethodsWe conducted a retrospective study, covering a 20-year period, comparing the type of physician first consulted by an ALS patient at the time of initial symptoms and the amount of time that elapsed to the final diagnosis of ALS. A total of 202 patients were diagnosed and stratified according to the onset of ALS symptoms (bulbar onset [BO] and limb onset [LO]). We noted the type of physician first seen by the patient. The diagnostic interval was calculated as the time between onset of symptoms and the final diagnosis of ALS.ResultsA total of 202 ALS patients were examined. Clinical BO and LO was observed in 78 (36.6%) and in 124 (61.4%) of these patients, respectively. The type of physician examining these patients at the first symptoms of disease was as follows (BO and LO): neurologist (38.5% and 25.8%), general practitioner (14.1% and 35.5%), orthopedist (12.8% and 35.5%), otolaryngologist (15.4% and 0%), and neurosurgeon (14.1% and 3.2%). Mean diagnostic interval (standard deviation) for patients with either set of symptoms was 13.1 (6.5) months; the diagnostic interval of patients with BO and LO was 9.2 (4.5) and 15.2 (7.7) months, respectively. ALS diagnosis in LO patients was delayed by more than 10 months when the patient first consulted an orthopedist rather than a neurologist.ConclusionMore than 50% of the ALS patients included in this study did not visit a neurologist at the first symptoms of disease onset. The diagnosis of ALS was prolonged in LO patients visiting an orthopedist. We speculate that this increase in the diagnostic interval in LO patients visiting an orthopedist was due to a lack of bulbar symptoms in the early stages of this disease.

Combined Treatment of Methylprednisolone Pulse and Memantine Hydrochloride Prompts Recovery from Neurological Dysfunction and Cerebral Hypoperfusion in Carbon Monoxide Poisoning: A Case Report

A 49-year-old healthy man developed sudden unconsciousness under inadequate ventilation. Blood gas analysis showed carboxyhemoglobin of 7.3%. After normobaric oxygen therapy, he recovered completely 7 days later. At 3 weeks after carbon monoxide (CO) exposures, memory and gait disturbances appeared. Neurological examination revealed Mini-Mental State Examination (MMSE) score of 5 of 30 points, leg hyper-reflexia with Babinski signs, and Parkinsonism. Brain fluid-attenuated inversion recovery imaging disclosed symmetric hypointense lesions in the thalamus and the globus pallidus, and hyperintense lesions in the cerebral white matter. Brain single-photon emission tomography (SPECT) scanning with (99m)Technesium-ethyl cysteinate dimer displayed marked hypoperfusion in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. He was diagnosed as CO poisoning and treated with hyperbaric oxygen therapy. The neurological deficits were not ameliorated. At 9 weeks after neurological onset, methylprednisolone (1000 mg/day, intravenous, 3 days) and memantine hydrochloride (20 mg/day, per os) were administered. Three days later, MMSE score was increased from 3 to 20 points. Neurological examination was normal 3 weeks later. Brain SPECT exhibited 20% increase of regional cerebral blood flows in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. These clinicoradiological changes supported that the treatment with steroid pulse and memantine hydrochloride could prompt recovery from neurological dysfunction and cerebral hypoperfusion. Further clinical trials are warranted whether such combined therapy can attenuate neurological deficits and cerebral hypoperfusion in patients with CO poisoning.

Intervention by Speech Therapists to Promote Oral Intake of Patients with Acute Stroke: A Retrospective Cohort Study

OBJECTIVE Early rehabilitation for acute stroke patients is widely recommended. We tested the hypothesis that daily intervention by speech therapists promotes safe oral intake of patients with acute stroke. METHODS We analyzed hospitalized patients who experienced cerebral infarction and cerebral hemorrhage and who underwent rehabilitation between October 2010 and September 2014 at our hospital. In total, 936 patients were analyzed, and 452 patients underwent daily speech therapy. We examined the association of training frequency and eating status. RESULTS Multiple linear regression analysis indicated that daily speech therapy was correlated significantly and positively with a reduction in the number of days of hospitalization until oral intake commenced (coefficient, -.998; 95% confidence interval, -1.793 to -.202; P < .05), and was not correlated with the cessation of oral intake due to aspiration pneumonia after resuming oral intake. CONCLUSION Our retrospective cohort study demonstrated that daily intervention by speech therapists in patients with acute stroke shortens the number of days until oral intake without increasing the incidence of aspiration pneumonia.

Incomplete Posterior Circle of Willis in Migraineurs With Aura

We read the article by Bugnicourt et al with great interest. Authors show that incomplete posterior circle of Willis (CW) is an independent risk factor of migraine. Our previous study disclosed that proportion of a fetal CW did not differ between migraine and control subjects. We also studied morphological changes of posterior CW in migraineurs, and we would like to compare between ours and the results of Bugnicourt et al. Among 141 migraine patients in our neurology department, 73 migraineurs (31 migraineurs with aura [MA] and 42 without aura [MO]) had brain MR imaging and angiography (MRA) using 3-dimensional time-of-flight sequence. A skilled neuroradiologist reviewed maximum intensity projection (MIP) imaging and source imaging of MRA. Complete posterior CW was defined as the presence of both posterior communicating arteries and both P1 segments of the posterior cerebral arteries. Other patterns of posterior CW were classified to incomplete type. CW morphology was compared between migraineurs and 100 age-matched control subjects (Table). Those participants who had hypertension, diabetes mellitus, dyslipidemia, or oral contraceptives were excluded. As compared with controls, migraineurs and MA sufferers significantly decreased the frequency of complete posterior CW. No significant changes of posterior CW existed between MO sufferers and controls. Posterior CW patterns were not correlated with other clinical aspects of migraineurs, including age, sex, onset age, and duration of migraine (Table). Incomplete posterior CW is associated with MA in our study whereas Bugnicourt et al showed no statistical differences of posterior CW patterns between MA and MO patients. The question arises whether incomplete posterior CW is a causative cofactor of migraine onset or whether these blood flow changes occur after migraine onset.We would like to know how onset age and duration of migraine influence posterior CW shapes in patients of Bugnicourt et al, as authors mention that their patients visit emergency department. Thirty of 47 migraineurs have atypical episodes, and 21 of 24 MA patients have prolonged aura more than 1 hour. Otherwise, our patients did not derive from emergency department. We excluded migraineurs with atypical episode or long visual aura. Posterior configuration of CW was assessed carefully by serial slices of source imaging in our subjects, besides