Takanori Takazawa

Neurobiology of Depression and Anxiety in Parkinson's Disease

Depression and anxiety are common in Parkinsons disease (PD) and have important consequences on quality of life. These have long been recognized as frequent accompanying syndromes of PD, and several reports suggest that these are the causative process or risk factors that are present many years before the appearance of motor symptoms. The neurochemical changes in PD involving dopamine, norepinephrine, and serotonin might be related to the pathophysiology of depression and anxiety, but this is still not clear. Several studies showed that anxiety in PD patients occurs earlier than depression, during premotor phase, suggesting that there may be a link between the mechanisms that cause anxiety and PD. Whereas a recent study reported that PD patients with depression and anxiety were associated with different demographic and clinical features.

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

(Headache 2011;51:1239‐1244)

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.

Relationship between cervical cord 1H-magnetic resonance spectroscopy and clinoco-electromyographic profile in amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons, leading to limb paralysis and respiratory failure. Methods: C1–C3 cord 1H‐magnetic resonance spectroscopy (1H‐MRS) was performed in 19 patients with ALS and 20 controls. N‐acetylaspartate (NAA), choline‐containing compounds, creatine plus phosphocreatine (Cr), and myo‐Inositol (m‐Ins) were measured. ALS Functional Rating Scale‐Revised (ALSFRS) and forced vital capacity (FVC) were assessed. The rates of decline were calculated at 6 months before and after 1H‐MRS. Results: NAA/Cr and NAA/m‐Ins were decreased significantly, and m‐Ins/Cr was increased significantly in ALS patients compared with controls. NAA/Cr and NAA/m‐Ins were correlated with ALSFRS and FVC and inversely linked to the decline rates. NAA/Cr, NAA/m‐Ins, and m‐Ins/Cr were altered markedly in 9 patients with denervation and neurogenic changes in both C2 paraspinal and upper limb muscles. Conclusions: These metabolite ratios were associated with disease progression and ongoing denervation in neck and hand muscles. C1–C3 cord 1H‐MRS might reflect anterior horn cell damage causing neck/arm weakness and respiratory dysfunction in ALS patients. Muscle Nerve, 2013

Wegener Granulomatosis-associated Optic Perineuritis

Abstract Introdunction: We report two patients with optic perineuritis (OPN) and hypertrophic pachymeningitis in Wegener granulomatosis (WG). Case report: Patient 1: a 74-year-old man developed blurred vision in each eye, sequentially, over a year. In the first episode, visual acuity in the right eye was reduced to no light perception, and in the second episode, the vision in the left eye fell to 20/100. Brain and orbital magnetic resonance imaging (MRI) revealed abnormal enhancement in the meninges and the ipsilateral optic nerve sheath. T2-hyperintense lesions were found along the outer rim of the ipsilateral optic nerve. Seropositive proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA), microhematuria and multiple pulmonary nodules suggested the diagnosis of WG. Steroid therapy was initiated 3 months after the first onset, but with no clinical response. At the 2nd episode, rapid administration of steroid ameliorated visual disturbance and MRI lesions markedly. Patient 2: a 72-year-old man developed blurred vision in each eye. Visual acuity measured no light perception in OD and 6/12 in OS. Gadolinium-enhanced MRI disclosed enhancement in the meninges and both optic nerve sheaths. T2-weighted imaging displayed hyperintense lesions along the outer rims of optic nerves. Otolaryngologic examination, seropositive PR3-ANCA and pulmonary nodules supported the diagnosis of WG. Steroid and cyclophosphamide treatment improved visual dysfunction and MRI lesions in the meninges and the optic nerve sheaths. Comment: The morphological similarity and the anatomical continuity between the meningeal and the perioptic tissues suggest that extension of granulomatous inflammation along such tissue planes accounted for visual loss in these two patients with WG.

Prevalence and Clinical Hallmarks of Primary Exercise Headache in Middle-aged Japanese on Health Check-up

Objective We examined the prevalence and clinical features of primary exercise headache (PEH) in middle-aged Japanese population. Methods A headache specialist interviewed middle-aged subjects serially on health check-up. The primary headaches were diagnosed according to the International Classification of Headache Disorders (ICHD-III beta). Cardiovascular disease (CVD) risk and radiological findings were analyzed. Prevalence of PEH and clinical features were assessed. Results Among 2,546 subjects (1,588 men and 958 women), thirty subjects (13 men and 17 women) were diagnosed with PEH. The prevalence of PEH was 1.19%, 0.82% in men and 1.77% in women. The mean age [standard deviation (SD)] of the subjects was 44.3 (8.8) years and their mean duration (SD) of PEH was 4.5 (7.0) months. Headache occurred bilaterally (23 patients) or unilaterally (7 patients), and in the occipital (16 patients), frontal (10 patients) or diffuse region (4 patients). The persistent headache time ranged from 5 minutes to 12 hours. The degree of headache severity was classified as mild (13 patients), moderate (5 patients) or severe degree (12 patients). PEH was triggered by gym training (16 patients), swimming (6 patients), running (6 patient) and skiing (2 patients). All patients were exercise beginners or played a sport occasionally. No patients visited physicians for headache consultation. Other primary headaches coexisted in 20 patients (67%). Twenty patients had migraine without aura (MO). Seven patients had headache associated with sexual activity. Five patients had cough headache. Two patients had CVD risk factors. Conclusion The present study of PEH indicated the prevalence of 1.2% and the female/male ratio of 2.1 in middle-aged Japanese. The comorbidity rate of MO was high. PEH may not be an uncommon headache in middle-aged MO sufferers and sport beginners.

Clinical Profile and Changes of Serum Lipid Levels in Epileptic Patients after Cerebral Infarction

BACKGROUND Antiepileptic drugs (AEDs) may increase development of dyslipidemia and cerebrovascular disease (CVD). We examined the clinical profile and changes of serum lipid levels after AED monotherapy in patients with poststroke epilepsy (PSE) after cerebral infarction (CI). SUBJECTS AND METHODS Medical records were reviewed in consecutive 2144 CI patients. Monotherapy of valproate, carbamazepine (CBZ), phenytoin (PHT), zonisamide, levetiracetam, or lamotrigine was performed in PSE patients. Serum lipid levels were measured before and at 3 months after AED treatment. RESULTS The prevalence of PSE was 7.0% in CI patients. The TOAST etiology disclosed large-artery atherosclerosis in 68 patients (45%), cardioembolism in 63 patients (42%), and undetermined cause in 19 patients (13%). CVD risk profile showed obesity of 18 patients (12%), current smoker of 30 patients (20%), hypertension of 75 patients (50%), diabetes mellitus of 32 patients (21%), dyslipidemia of 15 patients (10%), and atrial fibrillation of 63 patients (42%). CBZ or PHT administration increased serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels significantly compared to baseline and AED-untreated controls. Those levels were not increased significantly in other AED and control groups. Serum high-density lipoprotein-cholesterol and triglyceride levels did not differ statistically in all groups. CONCLUSIONS The prevalence of post-CI epilepsy was 7.0%. The pathogenesis contributed to atherothrombosis and cardioembolism. CBZ or PHT administration increased serum TC and LDL-C significantly. Thus, we should pay more attention to serum lipid levels in patients receiving cytochrome P450 (CYP)-induced AEDs, and might considerer switching to non-CYP-induced AEDs in patients with unfavorable serum lipid changes.

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

This study examined whether zonisamide (ZNS) cotreatment delays dopamine transporter (DAT) reduction on SPECT in Parkinson disease (PD) patients. The study participants met the following criteria: (i) age ≥ 40 years; (ii) HY stage = 2 or 3; (iii) average specific binding ratio (SBR) ≥2.00; (iv) levodopa administration without a prior history of ZNS use before the first DAT-SPECT (baseline). Attending physicians initially determined whether ZNS (25 mg/day) should be used or not. Levodopa and other anti-PD medications were not restricted. The second DAT-SPECT (endpoint) was conducted 1.2 ± 0.2 years after the first DAT-SPECT. Clinicoradiological changes of HY stage, UPDRS parts II to IV, dyskinesia subscore, and SBR were calculated. Statistical differences were analyzed by Students t-test, ANOVA, or multilogistic analysis. ZNS cotreatment improved wearing off and prevented the development of dyskinesia without additional administration of selegiline, entacapone, and dopamine receptor agonists. The endpoint SBR reduced significantly in the non-ZNS group compared to the baseline (P < .01). The SBR decline rate reduced significantly in the ZNS group (P < .01). ZNS was an independent preventive factor for SBR reduction. These results suggested a beneficial potential that ZNS preserves striatal presynaptic DAT expression and slows disease progression in early-stage PD.

Preventive Treatment with Lomerizine Increases Cerebral Blood Flows during the Interictal Phase of Migraine

BACKGROUND Changes in regional cerebral blood flow (rCBF) were reported in migraineurs. However, little is known how preventive medications of migraine can influence rCBF. Lomerizine, a calcium channel blocker, has been used for migraine prophylaxis in Japan. We examined rCBF after lomerizine treatment. SUBJECTS AND METHODS Migraine was diagnosed according to the criteria of the International Classification of Headache Disorders, Third Edition beta. Migraine subtype was classified into migraine with aura (MA) and migraine without aura (MO). Lomerizine (10 mg/day, per oral) was administered for 3 months. Headache Impact Test-6 (HIT-6) and blood pressure (BP) were compared at baseline and end point. Brain single photon emission computed tomography using 99mTc-ethyl cysteinate dimer was performed at the interictal period. Brain SPECT data were analyzed according to revised version of 3-dimensional stereotaxic region of interest template. Clinic-radiological variables were analyzed by paired Students t test. RESULTS Ten migraineurs (4 men and 6 women) participated in the present study. Mean age was 54.1 (standard deviation [SD] 10.1) years. Mean duration of migraine was 25.3 (SD 9.8) years. Migraine subtype showed 4 MA and 6 MO patients. Mean score of HIT-6 was 66.3 (SD 11.7). Lomerizine treatment decreased HIT-6 scores significantly (P < .01). BP did not differ significantly after lomerizine treatment. Lomerizine treatment increased rCBF 20% approximately in the frontal, the parietal, the temporal, and the occipital region. CONCLUSIONS The present study indicated a significant increase in interictal rCBF after lomerizine treatment in migraineurs. The upregulation of rCBF could contribute to the antimigraine mechanism of lomerizine.

Domperidone effective in preventing rivastigmine-related gastrointestinal disturbances in patients with Alzheimer's disease.

Objective While acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastig-mine, are beneficial in treating behavioral symptoms of patients with Alzheimer’s disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance. Materials and methods Thirty patients with mild-to-moderate AD (scores 10–22 on the MiniMental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake. Results After 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (≥4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (≤3) subgroups showed no changes during the dose-escalation phase. Conclusion For AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.