Kazuo Hashikawa

Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations

Background: Patients with Parkinson disease (PD) often experience visual hallucinations (VH) with retained insight (nonpsychotic) but the precise mechanism remains unclear. Objective: To clarify which neural substrates participate in nonpsychotic VH in PD, the authors evaluated regional cerebral blood flow (rCBF) changes in patients with PD and VH. Methods: The authors compared 24 patients with PD who had nonpsychotic VH (hallucinators) and 41 patients with PD who had never experienced VH (non-hallucinators) using SPECT images with N-isopropyl-p-[123I]iodoamphetamine. There were no significant differences in age, sex, duration of disease, doses of PD medications, Hoehn and Yahr scale, or Mini-Mental State Examination (MMSE) scores between the two groups. The rCBF data were analyzed using statistical parametric mapping (SPM). Results: The rCBF in the right fusiform gyrus was lower in the hallucinators than in the non-hallucinators (corrected p < 0.05 at cluster levels). The hallucinators revealed higher rCBF in the right superior and middle temporal gyri than the non-hallucinators (uncorrected p < 0.001). These significant differences were demonstrated after MMSE scores and duration of disease, which are the relevant factors associated with VH, were covariated out. Conclusions: Nonpsychotic visual hallucinations in Parkinson disease (PD) may be associated with hypoperfusion in the right fusiform gyrus and hyperperfusion in the right superior and middle temporal gyri. These temporal regions are important for visual object recognition and these regional cerebral blood flow changes are associated with inappropriate visual processing and are responsible for nonpsychotic visual hallucinations in PD.

Prefrontal hypofunction in patients with intractable mesial temporal lobe epilepsy

We compared the cognitive functions and interictal cerebral glucose metabolism of 11 patients with mesial temporal lobe epilepsy (MTLE) with frequent seizures to those of 10 patients with MTLE with rare seizures; the groups were matched for age, sex, education, IQ, and focus side. The frequent-seizure group had more set-shifting impairment that correlated with glucose hypometabolism in the prefrontal cortices. Our results suggest that frequent seizures in MTLE are associated with hypofunction of the prefrontal cortex.

Decrease in Cortical Benzodiazepine Receptors in Symptomatic Patients With Leukoaraiosis A Positron Emission Tomography Study

Background and Purpose— [11C]flumazenil (FMZ), a ligand that selectively binds to the central benzodiazepine receptor in the neuronal membrane, is useful for evaluating neuronal viability in a positron emission tomography (PET) scan. Using this ligand, we investigated whether there was a correlation between neuronal integrity in various brain structures and dementia in patients with leukoaraiosis. Methods— Twelve patients with extensive leukoaraiosis on magnetic resonance imaging were divided into groups of patients with or without dementia. Based on a 2-compartment, 2-parameter model that included metabolite-corrected arterial input and PET-measured cerebral radioactivity, the distribution volume of FMZ (FMZ-Vd) was calculated in various regions of interest by nonlinear curve fitting. Additionally, tracer kinetic analysis was applied for voxel-by-voxel quantification of FMZ-Vd, and data analysis was performed by statistical parametric mapping. Results— The presence of dementia was associated with a reduced FMZ-Vd in widespread areas of the cerebral cortex, including the bilateral frontopolar and frontal/insular areas, the left temporo-occipital border areas, and the left marginal cortical areas. Conclusions— Differences in neuronal integrity in the cerebral cortex might determine whether patients with leukoaraiosis become symptomatic or not.

Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer's disease

Donepezil is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderate Alzheimers disease (AD). Since behavioral symptoms severely affect quality of life for AD patients and their caregivers, predicting behavioral responses to donepezil will be useful in managing patients with AD. In this study, we analyzed 70 consecutive cases with mild to moderate AD. Caregivers were interviewed with the Neuropsychiatric Inventory for behavioral assessment and 4-point improvement at week 12 was accepted as a treatment response. Twenty-one (30.0%) patients showed a behavioral response, while 42 (60.0%) showed no behavioral change and 7 (10.0%) worsened. Dysphoria, anxiety and apathy significantly improved after treatment among the responder group. The baseline profile including age, sex, Mini-Mental State Examination (MMSE), the Alzheimers Disease Assessment Scale (ADAS-cog) and the Geriatric Depression Scale did not differ significantly among the three groups. Statistical Parametric Mapping analysis of single photon emission computed tomography (SPECT) images at baseline showed that cerebral blood flow in the premotor and parietotemporal cortices was significantly higher in the responder group than in the worse group. The present study suggested usefulness of SPECT imaging in the prediction of behavioral response to donepezil among AD patients even with similar psychiatric symptoms and cognitive functions.

Decreased cerebral blood flow and prognosis of Alzheimer's disease: a multicenter HMPAO-SPECT study.

Purpose: To determine the usefulness of brain perfusion SPECT for evaluating the severity and progression of Alzheimers disease (AD).Methods: Eighty-four AD patients were included. At entry,99mTc-HMPAO-SPECT, the Mini Mental State Examination (MMSE), Mental Function Impairment Scale (MENFIS), and the Raven Colored Progression Matrix (RCPM) were performed for all 84 patients. During the follow-up periods, two individual MMSE evaluations in 34 patients, two MENFIS evaluations in 30 patients, and two RCPM evaluations in 20 patients were performed. Based on the regions of decreased cerebral blood flow demonstrated on 3D-SSP images of SPECT, the cases were classified as type A (no decrease), type B (decreased blood flow in the parietal or temporal lobe), type C (decreased blood flow in the frontal lobe and parietal or temporal lobe), type Pc (decreased blood flow in posterior cingulate gyrus only), and “other types”. The types of decreased blood flow, scores on neuropsychological evaluations, and symptom progression were analyzed.Results: The MENFIS, MMSE, and RCPM scores were poorest in type C patients at entry. The degree of decrease of these scores during the follow-up periods was also greatest in type C. The greatest difference between patients with and without rapid progression in SPECT data of the mild AD patients (MMSE score ≥ 24) was in the frontal lobe.Conclusion: Decreased blood flow in the frontal lobe of AD patients is correlated not only with reduced cognitive function at the time of the evaluation but with rapid progression in the subsequent clinical course.

Quantification of nicotinic acetylcholine receptors in Parkinson's disease with 123I-5IA SPECT

We quantified in vivo brain nicotinic acetylcholine receptor (nAChR) distributions in patients with Parkinsons disease (PD) and evaluated correlations between nAChR distributions and clinical variables of the patients, especially dopaminergic medications. Ten patients with PD without dementia underwent 5-(123)I-iodo-3-(2(S)-azetidinylmethoxy)pyridine ((123)I-5IA) single photon emission computed tomography (SPECT) and the data were compared with those of 10 age-matched healthy volunteers. Correlation analyses between (123)I-5IA distribution volumes (DVs) in each brain region and clinical variables of the patients were also performed. The PD group showed a statistically significant decrease (20-25%) in the brainstem and frontal cortex as compared with the control group. Although age, duration of disease, daily dose of levodopa, duration of PD medication use, and scores on the motor section of Unified Parkinsons Disease Rating Scale were not significantly correlated with DV values in any brain regions, high daily doses of dopamine agonist showed a significant negative correlation with DVs in the cerebellum, and temporal, parietal and occipital cortices. These findings suggest that patients with PD without dementia can show reductions especially in the brainstem and frontal cortex. They also suggest that dopamine agonists can have a negative influence on the distribution of nAChRs.

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

The peripheral benzodiazepine receptor (PBR) is a 18xa0kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [11C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson’s disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [11C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.

Motor cortex stimulation for levodopa-resistant akinesia: Case report

We treated a patient with levodopa‐resistant akinesia with motor cortex stimulation (MCS), and she showed dramatic improvement more than 1 year. On admission, the patient presented severe akinesia and gait disturbance without tremor and rigidity, and did not respond to levodopa test. The patient was suspected pure akinesia and progressive supranuclear palsy. First, high‐frequency rTMS of primary motor cortex was examined, and showed the dramatic improvement. Next, chronic subdural electrodes were implanted over the motor cortex bilaterally. One year after surgery, the Unified Parkinsons Disease Rating Scale had improved remarkably, and she could walk four times faster than before. The H215O PET study showed a significant increase of rCBF in the left SMA and right dorsolateral prefrontal cortex after bilateral MCS. MCS may be an alternative treatment for patients with akinesia, including those with PD, and particularly for levodopa‐resistant patients, who respond well to rTMS.

Comparison of striatal dopamine D2 receptors in Parkinson's disease and progressive supranuclear palsy patients using 〔123I〕 iodobenzofuran single-photon emission computed tomography

Background and Purpose. To investigate the clinical applicability and validity of [123I] iodobenzofuran (IBF) single‐photon emission computed tomography (SPECT), the authors analyzed the changes in striatal dopamine D2 receptor binding among 7 patients with Parkinsons disease (PD), 6 patients with progressive supranuclear palsy (PSP) (Hoehn and Yahr stage II to IV), and 8 normal controls. Methods. SPECT data were acquired every 1 minute for 60 minutes postinjection of 167 MBq [123I] IBF. The binding potential (BP) of the striatum was evaluated by 2 methods: region‐of‐interest (ROI) analysis by the nonlinear least squares method using blood sampling and time‐series brain radioactivities in normal controls and a voxel‐by‐voxel method based on a region model that provided parametric images of BP without blood sampling. Results. Statistical parametric mapping indicated that BP in the striatum of PSP patients was significantly lower than that of PD patients and normal controls (P <.005, uncorrected), and there was no significant difference between PD patients and normal controls, even in patients with PD at an advanced stage. Data derived from the ROI method and a simplified reference region model showed good correlations in normal controls, indicating the validity of the latter model. Conclusions. The results predict that [123I] IBF SPECT, especially voxel‐by‐voxel BP parametric imaging, can discriminate among extrapyramidal diseases such as PD and PSP and may be applicable for clinical use.

Association of vascular parkinsonism with impaired neuronal integrity in the striatum.

Summary.The purpose of this study is to identify the underlying differences between patients with white matter lesions (WMLs) who manifested gait disturbance suggestive of vascular parkinsonism (VaP) and those who did not, using the PET scan. Fourteen patients with extensive WMLs, as determined by MRI, were divided into two groups – 7 with gait disturbance and 7 without it. Neuronal integrity was evaluated with a PET scan using [11C]flumazenil (FMZ) by calculating the distribution volume of FMZ (FMZ-Vd) in various regions of interest by non-linear curve fitting. Additionally, tracer kinetic analysis was applied for voxel-by-voxel quantification of FMZ-Vd and data analysis was performed using statistical parametric mapping. The striatal FMZ-Vd values were inversely correlated with the motor UPDRS scores (r = 0.70, p < 0.005), and their reductions were associated with the presence of gait disturbance. Therefore, differences in neuronal integrity in the striatum may determine whether patients with WMLs develop VaP or not.