Clinical features and varieties of non-motor fluctuations in Parkinson's disease: A Japanese multicenter study

ObjectiveThis multicenter cross-sectional study aimed to investigate the clinical features and varieties of non-motor fluctuation in Parkinson's disease (PD).MethodsTo identify motor and non-motor fluctuation, we employed the wearing-off questionnaire of 19 symptoms (WOQ-19) in 464 PD patients. We compared the frequency of levodopa-related fluctuation as identified by the WOQ-19 with recognition by neurologists. We compared patients with both motor and non-motor fluctuations with those who only had motor fluctuations. Non-motor fluctuations were separated into psychiatric, autonomic, and sensory categories for further analysis.ResultsThe patients' average age was 70.8 ± 8.4 years (mean ± SD) and disease duration was 6.6 ± 5.0 years. The frequency of motor fluctuations was 69% and for non-motor fluctuation 40%. Fifty-three percent of patients with motor fluctuations also had non-motor fluctuations, whereas 93% of patients with non-motor fluctuations also had motor fluctuations. The WOQ-19 showed a sensitivity of 82% but a specificity of only 40%. The patients with both non-motor and motor fluctuations exhibited more severe motor symptoms, more non-motor symptoms and higher levodopa daily doses (p < 0.05). Patients had significantly higher fluctuation rates if they had psychiatric (49%) and sensory (45%) symptoms than patients with autonomic symptoms (32%, p < 0.01). Forty-eight percent of patients with non-motor fluctuations exhibited more than one type of non-motor fluctuation.ConclusionForty percent of PD patients presented with non-motor fluctuations, and almost half of these exhibited more than one type. Appropriate recognition of levodopa-related fluctuations, both motor and non-motor, can lead to treatment modifications in PD patients.     

Identification of synaptic activity-dependent genes by exposure of cultured cortical neurons to tetrodotoxin followed by its withdrawal

Activity-dependent gene expression is one of the key mechanisms of synaptic plasticity that form the basis of higher order functions such as learning and memory. In the present study, we surveyed for activity-dependent genes by analyzing gene expression changes accompanying reversible inhibition of synaptic activity by tetrodotoxin (TTX) using two types of DNA microarrays; our focused oligo DNA microarray "Synaptoarray" and the commercially available high-density array. Cerebral cortical cells from E18 rat embryos were cultured for 14 days to ensure synaptogenesis, then treated with 1 muM TTX for 48 hr without detectable effect on cell viability. Synaptic density estimated by the amount of Synapsin I and Synaptotagmin I was decreased 21-24% by TTX treatment, but recovered to the control level 48 hr after TTX withdrawal. Comparison of gene expression profiles by competitive hybridization of fluorescently labeled cRNA from TTX-treated and control cells showed an overall downregulation of the genes on the Synaptoarray by TTX-treatment with different recovery rates after TTX withdrawal. With 16 representative genes, microarray data were validated by real-time PCR analysis. Genes most severely downregulated by TTX and upregulated above the control level at 5 hr after TTX withdrawal were munc13-1 (involved in docking and priming of synaptic vesicles) and Shank2 (involved in the postsynaptic scaffold). In addition, comprehensive screening at 5 hr after TTX withdrawal using high density arrays resulted in additional identification of Rgs2, a regulator of trimeric G-protein signaling, as an activity-dependent gene. These three genes are thus likely to be key factors in the regulation of synaptic plasticity. (c) 2007 Wiley-Liss, Inc.     

Oxygen extraction fraction and acetazolamide reactivity in symptomatic carotid artery disease

Objective: It has been proposed that cerebral blood flow (CBF) response to acetazolamide may be reduced according to the degree of autoregulatory vasodilation in regions with normal oxygen extraction fraction (OEF), whereas the CBF response may be absent in regions with increased OEF where vasodilation may be maximal in response to reduced perfusion pressure. The objective of this study was to test this hypothesis.

Methods: Positron emission tomography (PET) was used to study 30 symptomatic patients with carotid artery steno-occlusive lesions. CBF at baseline and 10 minutes after an intravenous injection of 1 g acetazolamide was measured. The correlation between the change in CBF during acetazolamide administration and the baseline value of OEF in the affected hemisphere was examined.

Results: The baseline OEF value was inversely and non-linearly correlated with the percentage change in CBF during acetazolamide administration (R² = 0.25, p = 0.02). There was an upward trend of OEF with diminishing acetazolamide response below a critical level around zero response. Acetazolamide response less than 6.65% over baseline (sensitivity 100%, specificity 89%, positive predictive value 50%, negative predictive value 100%) was established as most helpful in predicting abnormally high OEF.

Conclusions: The inverse, non-linear relationship between OEF and CBF response to acetazolamide suggests that these two measurements may not identify haemodynamic impairment in the same patients.

     

Transgenic expression of the protein-L-isoaspartyl methyltransferase (PIMT) gene in the brain rescues mice from the fatal epilepsy of PIMT deficiency

Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues. In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. The mutant mice also showed a neurodegenerative pathology in hippocampi and impaired spatial memory. Still undefined, however, is how the accumulation of isoaspartates leads to the death of PIMT-deficient mice. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT deficiency. Rescue experiments showed that Tg expression of PIMT driven by a prion promoter effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially rescued line, the mice survived. Interestingly, synapsin I, which was extensively modified posttranslationally in PIMT-deficient mice, was specifically repaired in a partially rescued, but symptom-improved, Tg line. Our results suggest that an overall accumulation of damaged proteins does not necessarily lead to a fatal epileptic seizure, whereas certain modifications, such as changes in synapsin I, may play a pivotal pathological role in epilepsy.     

Medial temporal lobe activation during context-dependent relational processes in episodic retrieval: an fMRI study. Functional magnetic resonance imaging

Previous studies have reported that the medial temporal lobe (MTL) structures contribute to the processing of relations among multiple stimuli in episodic encoding. There have been few studies, however, on the episodic retrieval requiring processing of relations among multiple components that was involved in our events. We used functional magnetic resonance imaging (fMRI) to investigate neural activities during the retrieval of relations within an organized episode and the recognition of an episodic component. Healthy, normal participants memorized 50 four-scene comic strips before fMRI scanning. In the retrieval phase with fMRI scanning, participants were engaged in three tasks: a visual identification (VI) task, a story recall (SR) task, and a picture recognition (PRe) task. In the VI task, participants were asked to judge whether they could identify at least one female character in the two scenes presented vertically. In the SR task, participants were shown the first and last scenes from strips memorized previously and asked to judge whether or not the two scenes were from the same strip. In the PRe task, participants were shown two scenes and asked to judge whether they both belonged to the memorized scenes. The two contrasts of SR with VI and PRe with VI demonstrated some commonly activated areas, such as the bilateral middle frontal gyrus and cerebellum. More importantly, the SR task differentially activated the bilateral parahippocampal gyrus, whereas the PRe task differentially activated right prefrontal areas, including the inferior frontal and precentral gyri. The results suggest that the activity of the MTL structures may be strongly associated with episodic memory retrieval requiring context-dependent relational processing.     

A novel AMPA receptor antagonist, YM872, reduces infarct size after middle cerebral artery occlusion in rats

The neuroprotective effect of YM872 ([2.3-dioxo-7-(1H-imidazol-1-yl) 6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate), a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middle cerebral artery (MCA) occlusion using the intraluminal suture occlusion method for 24 h. YM872 was intravenously infused for 4 h (20 and 40 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA occlusion, to investigate the effect of prolonged duration of the treatment on infarct volume. In the 4 h infusion study, YM872 reduced the cortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not significantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h infusion study, however, YM872 markedly reduced the cortical infarct volume by 62%, even at 20 mg/kg/h. The present study indicates that the neuroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment with AMPA antagonists following focal cerebral ischemia. YM872, a highly water soluble compound, is applicable to investigate the role of AMPA receptors in ischemic models without concern about nephrotoxicity and could be useful in the treatment of human stroke.     

Effects of dibutyryl cyclic AMP and forskolin on phospholipid biosynthesis in thrombin-stimulated human platelets

The influence of forskolin, an adenylate cyclase activator, and of dibutyryl cyclic AMP (Bt2cAMP) on [3H]glycerol incorporation into glycerolipids was investigated in human platelets. It was found that preincubation with 2.5 mM Bt2cAMP produced a 2-4-fold increase in thrombin-induced incorporation into phospholipids compared to platelets activated by thrombin alone. Pretreatment with forskolin, which increased cellular cAMP content, also resulted in an increase in thrombin-stimulated [3H]glycerol incorporation into phospholipids. These findings demonstrate that a rise in platelet cAMP can accentuate thrombin-induced de novo synthesis of phospholipids from [3H]glycerol. Since the content of cellular cAMP was correlated with its ability to inhibit platelet activation monitored by serotonin release, it seems likely that glycerolipid, in particular phospholipid biosynthesis, is involved in controlling platelet activation by thrombin.     

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases

Eomesodermin-expressing (Eomes⁺) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes⁺ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes⁺ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes⁺ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes⁺ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093–1098     

Temporal lobe gray matter in schizophrenia spectrum: a volumetric MRI study of the fusiform gyrus, parahippocampal gyrus, and middle and inferior temporal gyri

Although several brain morphologic studies have suggested abnormalities in the temporal regions to be a common indicator of vulnerability for the schizophrenia spectrum, less attention has been paid to temporal lobe structures other than the superior temporal gyrus or the medial temporal region. In this study, we investigated the volume of gray matter in the fusiform gyrus, the parahippocampal gyrus, the middle temporal gyrus, and the inferior temporal gyrus using magnetic resonance imaging in 39 schizotypal disorder patients, 65 schizophrenia patients, and 72 age and gender matched healthy control subjects. The anterior fusiform gyrus was significantly smaller in the schizophrenia patients than the control subjects but not in the schizotypal disorder patients, while the volume reduction of the posterior fusiform gyrus was common to both disorders. Volumes for the middle and inferior temporal gyri or the parahippocampal gyrus did not differ between groups. These findings suggest that abnormalities in the posterior region of the fusiform gyrus are, as have been suggested for the superior temporal gyrus or the amygdala/hippocampus, prominent among the temporal lobe structures as a common morphologic substrate for the schizophrenia spectrum, whereas more widespread alterations involving the anterior region might be associated with the development of full-blown schizophrenia.