Yoshinori Kajimoto

Effects of T-type calcium channel blockers on a parkinsonian tremor model in rats

T-type calcium channels are strongly associated with the generation of rhythmic firing patterns in the CNS. Blockers of these channels may have therapeutic potential for treating various types of tremor. The present study aimed to study the effects of a range of T-type calcium channel blockers in a parkinsonian tremor model in rats. We tested the effects of several T-type calcium channel blockers, including zonisamide (ZNS), ethosuximide, lomerizine, amiloride, mibefradil, and NCC 55-0396, a mibefradil derivative, on tacrine-induced tremulous jaw movements (TJMs), an animal model of parkinsonian tremor. Among the tested drugs, only ZNS and NCC 55-0396 significantly suppressed TJMs when given at a non-sedating dose. The transitivity of drugs to the central nervous system (CNS) may at least partially explain their differential anti-TJM effects. However, further studies are necessary to reveal other factors, since ethosuximide failed to show anti-TJM effects despite being known to cross the blood brain barrier. The present results suggest that T-type calcium channels in the CNS may be a suitable target for developing new therapeutic strategies for treating parkinsonian tremor.

Combination of transcranial sonography, olfactory testing, and MIBG myocardial scintigraphy as a diagnostic indicator for Parkinson's disease.

Background:  Appropriate diagnostic biomarkers are useful for improving speed and accuracy of a diagnosis. Substantia nigra (SN) hyperechogenicity visualized by transcranial sonography (TCS), olfactory dysfunction, and the reduced uptake of 123I‐metaiodobenzylguanidine (MIBG) in myocardial scintigraphy have been suggested as potential biomarkers for the identification of Parkinson’s disease (PD).

Transcranial sonography of the substantia nigra and MIBG myocardial scintigraphy: complementary role in the diagnosis of Parkinson's disease.

Both transcranial sonography (TCS) of the substantia nigra (SN) and metaiodobenzylguanidine (MIBG) myocardial scintigraphy have been determined to be useful for the diagnosis of Parkinsons disease (PD). In the present study, we performed both tests in 65 consecutive Japanese patients with idiopathic PD. In 30 PD patients (46.2%), the midbrain was adequately displayed by TCS allowing quantitative measurements of SN hyperechogenic areas. No significant correlation was found between the area of SN echogenicity and the reduction of myocardial uptake of MIBG. However, if the cut-off value was appropriately set, 29 patients (97%) were identified as abnormal by combined TCS and MIBG myocardial scintigraphy. Since TCS and MIBG myocardial scintigraphy can distinctively detect PD-related pathological phenomenon, it is expected that the combination of these tests could contribute to an accurate diagnosis of PD.

White matter hyperintensities in patients with multiple system atrophy

INTRODUCTION Although white matter hyperintensities (WMHs) are prevalent in the elderly, the clinical significance and the underlying pathophysiological mechanisms of WMHs in neurodegenerative disorders have not been fully clarified. OBJECTIVE The present study aimed to determine the degree of WMHs in patients with multiple system atrophy (MSA), and analyze the predisposing factors for WMHs. METHODS Two raters blinded to clinical information assessed cerebrovascular lesions in brain MRIs from patients with MSA and age-matched controls. Patients with Parkinsons disease (PD) were similarly studied as a disease control. The results obtained were compared with the clinical characteristics of the patients and statistically analyzed. RESULTS WMHs in patients with MSA were statistically greater compared with PD patients or controls. There were no significant differences in either lacunar or territorial infarcts. Multiple linear regression analysis demonstrated that age, supine systolic blood pressure, and a drop in orthostatic blood pressure were significantly and independently correlated with WMH scores in MSA. CONCLUSIONS The present study suggests that white matter is differentially involved in MSA. In addition to aging, cerebral hypoperfusions caused by fluctuations of blood pressure may be a significant contributing factor to WMHs in MSA, although the possibility that degenerative processes occurring in oligodendrocytes may be associated with WMHs should not be excluded.

T2-low signal intensity in the cortex in multiple system atrophy

To determine the clinical significance of T2-low signal intensity in the cortex of patients presenting parkinsonism, T2-weighted magnetic resonance (MR) images of the cortex of patients with multiple system atrophy (MSA), Parkinsons disease (PD) and progressive supranuclear palsy (PSP), and compared with those of patients with amyotrophic lateral sclerosis (ALS) and age-matched normal controls. The MR images were gathered and presented randomly to three neurologists who were blind to information on the patients. There was a significant increase in the frequency of T2-low signal intensity in the cortex of patients with ALS and MSA. Particularly in those with MSA, the T2-low signal intensity was observed not only in the motor cortex but also in the frontal association cortex. The cortical T2-low signal intensity in MSA might reflect the spread of degenerative processes in the cortex.

Sensorimotor hemiparesis with secondary cervical dystonia following lateral caudal medullary infarction without signs and symptoms of Wallenberg syndrome

We report the case of an 84-year-old woman who suddenly developed motor and both superficial and deep sensory hemiparesis on the left side, and cervical dystonia with a head tilt to the right side. A brain MRI showed an infarct in the left lateral caudal medulla. It is clinically important to recognize that the lateral caudal medullary infarction appears without signs and symptoms of lower cranial nerve palsies commonly involved in Wallenberg syndrome.

Transcranial sonography in relation to SPECT and MIBG.

Neuroimaging techniques have substantially progressed over the past several years. These developments have provided new information about the degenerative processes involved in Parkinsons disease (PD). Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even in preclinical stages. Myocardial scintigraphy with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has been used to assess cardiac sympathetic function, and recent studies have revealed that the cardiac uptake of MIBG is significantly reduced in patients with PD and Lewy body dementia. In addition, substantia nigra (SN) hyperechogenicity, detected with transcranial sonography (TCS), might provide a marker of susceptibility to PD. We briefly review data regarding the clinical significance of these functional imaging studies in the diagnosis of PD, and discuss the diagnostic potential of the combining TCS of the SN with other functional imaging tools.

Transcranial sonography of the substantia nigra in patients with Parkinson's disease

Transcranial sonography (TCS) of the substantia nigra (SN) is becoming a tool for the diagnosis of Parkinsons disease (PD), particularly in the early phase of illness. SN hyperechogenicity is a characteristic finding in patients with PD, and can be observed in about 90% of cases. Hitherto reported studies, as well as our own experience, have revealed that SN hyperechogenicity is less frequently observed in healthy subjects or patients with atypical parkinsonism, such as progressive supranuclear palsy and multiple system atrophy, suggesting that TCS of SN can be used to make an early differentiation between PD and atypical parkinsonism. The size of SN hyperechogenicity does not change during the course of PD, suggesting that this finding does not result simply from cell death or neurodegeneration. Although the exact cause of SN hyperechogenicity remains fully undetermined at present, increased iron content may play a key role, because post mortem analysis revealed that iron and ferritin content in the SN correlated positively with SN hyperechogenicity. Further studies are necessary to establish the diagnostic accuracy of TCS of the SN, because there may be inter-rater or inter-laboratory variability in TCS. Although further basic and clinical research is required, it is expected that TCS will be a useful tool for the clinical diagnosis of PD or related disorders. In addition, although most healthy subjects with SN hyperechogenicity will not develop PD, TCS of the SN would be potentially helpful for preclinical diagnosis of PD in subjects at risk.

Experimental analysis of anti-parkinsonian effects of zonisamide

the role of -syn in the axonal pathology, Thy-1 promoter driven -syn transgenic (Tg) mice were analyzed by histological procedures. Two types of -syn accumulated abnormal axon structures, possibly synaptic swellings, were observed in the brains of 18 months old Tg mice but not in the control mice. One was with about 2 m diameter structure, which was immunopositive for vesicular glutamate transporter. The other had 4 m or more diameter and was immunostained with glutamic-acid decarboxylase. Interestingly, calbindin was positive only in the larger type of swelling. Further ultrastructural characterization of these two types of -syn accumulated terminals is in progress. Our results suggest that at least two types of axonal pathology may be brought about by -syn accumulation in the Tg mice brain.