A descriptive study of Parkinson disease and atypical parkinsonisms in the Annuals of the Pathological Autopsy Cases in Japan.

Although many entities have been established within the broad spectrum of Parkinson disease (PD) and atypical parkinsonisms, they are often difficult to differentiate. To clarify the current clinical diagnostic conditions and problems in PD and atypical parkinsonisms, we analyzed volumes of the Annuals of the Pathological Autopsy Cases in Japan. Among 130 105 autopsies conducted from 2007 to 2016 throughout Japan, patients were included in the study if they had been either clinically or pathologically diagnosed with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Autopsy rates were 6.4% for clinically diagnosed PD, 34.1% for MSA, 16.3% for PSP, and 17.4% for CBD. The specificities and sensitivities of clinical diagnoses were 88.0% and 82.0% for PD, 95.2% and 86.0% for MSA, 82.7% and 73.2% for PSP, and 55.4% and 57.7% for CBD, respectively. Clinical diagnoses had relatively high accuracy, but low autopsy rates are of concern. Many patients with rarer disorders were clinically misdiagnosed with PD, a more common disorder. Autopsy rates, irrespective of specific disorders, should be increased to detect rare diseases. Increasing autopsy rates will increase the available clinical information regarding pathologically confirmed patients and contribute to more accurate clinical diagnoses.

Effects of repetitive transcranial magnetic stimulation on cerebral glucose metabolism.

OBJECTIVE: To investigate the mechanisms underlying the effect of repetitive transcranial magnetic stimulation (rTMS) on post-stroke hemiplegia, we assessed alterations in cerebral glucose metabolism. METHODS: Five post-stroke hemiplegic patients (three targeted for upper limb impairment and two targeted for lower limb impairment) aged 62.6 ± 6.1 years (mean ± standard deviation) with a duration since stroke onset of 3.5 ± 3.8 years participated in this preliminary study. Cerebral glucose metabolism was measured twice-before and after rTMS with intensive rehabilitation-using positron emission tomography with [18F]fluorodeoxyglucose. The Asymmetry Index (AI) was calculated to assess laterality of metabolism between the lesional and contralesional motor areas. The alteration rates of AI (%ΔAI) were compared between participants in whom rTMS was effective and ineffective. RESULTS: Two of the three upper-limb-targeted patients and one of the two lower-limb-targeted patients showed motor function improvements following rTMS treatment. All three patients who responded to rTMS had improved laterality of cerebral glucose metabolism in motor areas, commonly in the precentral gyrus, with an %ΔAI of approximately 10%. In contrast, the two patients who did not respond to rTMS had no improvements in laterality. CONCLUSIONS: These results suggest for the first time that improved glucose metabolism is associated with improved motor function after a combination of rTMS and intensive rehabilitation.

Frontotemporal lobar degeneration in the "Annual of the Pathological Autopsy Cases in Japan".

BACKGROUND: Good accuracy for the clinical diagnosis of frontotemporal lobar degeneration (FTLD) by specialists in an early onset dementia clinic has been reported. OBJECTIVE: To assess the diagnostic accuracy of FTLD in an entire population, without restrictions related to patient age or diagnosing physician. METHODS: Volumes of the "Annual of the Pathological Autopsy Cases in Japan," with reports of 130,105 autopsies throughout Japan from 2007 to 2016, were descriptively analyzed. RESULTS: There were 219 patients with clinical and/or pathological diagnoses of FTLD. The sensitivity and specificity were 24.5% and 76.9%, respectively. Age at death for pathologically confirmed patients was 76.3 ± 11.6 years (mean ± standard deviation). Overlooked patients died significantly older than patients with an accurate clinical diagnosis. CONCLUSIONS: Clinical diagnoses of FTLD had low sensitivity. Furthermore, the age at death of pathologically confirmed patients suggests that FTLD affects a wide age range and is not restricted to presenile individuals.

Prion diseases reported in the "Annual of the Pathological Autopsy Cases in Japan".

BACKGROUND: For surveillance projects to be successful, it is important to accurately diagnose all patients, without overlooking any cases. Here, we investigated the present clinical diagnostic accuracy for prion diseases in Japan. METHODS: We analyzed volumes of the "Annual of the Pathological Autopsy Cases in Japan", which reported details on 130,105 autopsies conducted from 2007 to 2016 throughout Japan. RESULTS: The clinical diagnosis of patients with prion disease had a specificity of 91.3% and a sensitivity of 96.3%. The autopsy rates were estimated as 17.8% for patients with clinically suspected prion disease and as 1.8% for the entire population. CONCLUSIONS: Despite the good accuracy of clinical diagnoses of prion diseases, a calculated 78.4 patients with prion disease were expected to have gone undiagnosed during the 10-year study period. However, autopsy is estimated to reveal a maximum of only 13.8 of these clinically undiagnosed patients because of the low autopsy rate. The overall autopsy rate, irrespective of any specific disorder, must increase for effective surveillance projects of disease incidence to be conducted.

Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism.

BACKGROUND: Although pure cerebellar ataxia is usually emphasized as the characteristic clinical feature of spinocerebellar ataxia type 6 (SCA6), parkinsonism has been repeatedly described in patients with genetically confirmed SCA6. METHODS: We conducted a positron emission tomography study using a combination of [18F]fluoro-L-dopa for dopamine synthesis and [11C]raclopride for dopamine D2 receptor function on six genetically confirmed SCA6 patients, both with and without parkinsonism. To the best of our knowledge, this is the first dopamine receptor imaging study of patients with SCA6. RESULTS: Most patients had somewhat decreased dopaminergic function, and this decrease was significant in the caudate nucleus. In addition, one SCA6 patient with parkinsonism had whole striatal dysfunction of both dopamine synthesis and dopamine D2 receptor function. CONCLUSIONS: The pathology of SCA6 may not be restricted to the cerebellum, but may also be distributed across various regions, including in both presynaptic and postsynaptic dopaminergic neurons to some degree. Patients with SCA6 may show apparent parkinsonism after the progression of neurodegeneration.

Effects of pitavastatin on cerebral blood flow.

BACKGROUND: Hypercholesterolemia has been identified as an important risk factor for stroke. It has been reported that statins might reduce the risk for new or recurrent cardiovascular events and strokes. OBJECTIVE: This paper reports on the effects of pitavastatin on cerebral blood flow in 2 elderly patients. CASE SUMMARY: Two patients, a 72-year-old right-handed Japanese man and a 77-year-old right-handed Japanese woman, both with a history of cerebral infarction, received 6-month treatment with pitavastatin 2 mg/d for complicated hypercholesterolemia. To assess regional cerebral blood flow (rCBF), single-photon emission computed tomography (SPECT) studies with technetium-99m-ethyl cysteinate dimer were carried out before and after pitavastatin administration. Tomography was evaluated using the Easy z Score Imaging System. None of the patients' other treatments, with the exception of pitavastatin initiation, were modified during the treatment period. In both patients, serum total cholesterol concentrations were improved within 3 months of initiation of pitavastatin treatment, with no marked changes in clinical symptoms. In both patients, improvement was found in rCBF on SPECT. The z score of the left parietal lobe in 1 patient was improved, from 2.20 to 1.69. That of the other patient was also improved, from 2.42 to 1.94. CONCLUSION: In both patients, clinically significant improvement in rCBF was found after 6-month treatment with pitavastatin 2 mg/d.

Stimulation of adenosine A1 receptors decreases in vivo dopamine D1 receptor binding of [11C]SCH23390 in the cat striatum revealed by positron emission tomography.

It has been previously suggested that activation of adenosine A1 receptor modulates dopamine D1 receptor binding in vitro, although the direct mechanism of this interaction in vivo has not yet been demonstrated. Here, we conducted a positron emission tomography (PET) study to demonstrate in vivo the interaction between these receptors. The specific adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) was acutely administered to cats under anesthetized condition. Cats underwent repeated measurement of striatal and cerebellar radioactivity following intravenous injection of dopamine D1 receptor-specific [11C]SCH23390. The pretreatment with CPA decreased the striatum/cerebellum ratio of the uptake of [11C]SCH23390. Using the cerebellar radioactivity as an input function, kinetic analysis was performed and demonstrated that CPA caused about 40% decrease in the association rate constant. These results suggest that stimulation of adenosine A1 receptors modulates dopamine D1 receptor binding in vivo.

An atlas-based image registration method for dopamine receptor imaging with PET in rats.

For analysis of in vivo dopamine receptor binding in the rat brain by positron emission tomography (PET), a convenient method to obtain precise anatomical registration for striatum and cerebellum on the PET image was developed. On the PET measurements, a control, an anesthetized rat was positioned in a stereotaxic holder so that the horizontal plane of the PET image would be parallel to the horizontal plane of the brain atlas. After the positioning, [11C]raclopride was intravenously injected into the rats and scanned to obtain PET images of dopamine D2 receptor in the brain. The striatum was bilaterally identified in the obtained PET image. The atlas-based regions of interest (ROIs) of the whole brain were preliminarily created according to the atlas, and were superimposed on an early phase PET image. The early phase PET image was compatible to the whole brain ROI in the atlas, which enabled determination of striatal and cerebellar ROI difficult to determine by the PET image alone. Using the cerebellar radioactivity as a reference input function, rate constants between the free/nonspecific compartment and the receptor bound compartment (k3 and k4) were calculated by a two-parameter compartment model, and the binding potential (k3/k4) was estimated. The binding potential and its coefficients of variation were 1.56+/-0.30, 19.3% in Wistar rats, 1.05+/-0.14, 13.4% in Sprague-Dawley (SD) rats, and 1.29+/-0.07, 5.2% in Fischer F344 rats, in which binding potential in Wistar rats was significantly higher than that in SD rats. This method is objective and convenient in routine use for PET studies in rats, regardless of differences in the rat strains.

[Therapeutic outcome of onabotulinum toxin type A in patients with upper limb spasticity].

Onabotulinum toxin type A treatment for post-stroke upper limb spasticity was investigated to contribute to establishing a standard dosage for Japanese patients. A total of 100 patients participated in the study. The outcome one month (33.6±6.5 days) after the treatment was assessed by the Modified Ashworth Scale (MAS) to estimate the mean effect with a 10-unit injection and the standard dosage expected to improve MAS 1 degree. Average improvement of 263 muscles treated with a higher concentration of 10 units diluted in 0.2 ml was 0.207±0.414 degrees, and that of 231 muscles treated with a lower concentration of 10 units in 0.4 ml was 0.149±0.244 degrees without significant difference among diluted concentrations. To improve MAS 1 degree, 64.6±31.1 units were required for the pectoralis major, 51.2±21.3 units for the teres major, 111.7±48.0 units for the biceps brachii, 51.6±26.8 units for the brachioradialis, 54.1±23.2 units for the brachialis, 34.4±10.7 units for the pronator teres, 64.6±27.9 units for the flexor carpi radialis, 62.4±26.8 units for the flexor carpi ulnalis, 58.5±31.1 units for the flexor digitorum profundus, 69.7±35.1 units for the flexor digitorum superficialis, 24.6±13.4 units for the flexor pollicis longus, and 15.6±11.3 units for the adductor pollicis. Although the results shown here had no significant differences among concentrations, increasing the volume would disturb injection into small muscles, so we considered that a lower volume with a higher concentration should assure larger benefits. It is difficult to make effective injections into all spastic muscles within the officially permitted health insurance dosage of 240 units. Hence, it is advisable to increase the applicable upper limit based on safely achieved cumulative experience.

Increased binding potential of [(11)C]raclopride during unilateral continuous microinjection of nicotine in rat striatum observed by positron emission tomography.

Nicotine injections and nicotine skin patches significantly improve attention, memory, and learning in Alzheimer's disease. In animal studies, nicotine improves the performance of various memory-related tasks, an effect that is thought to be mediated by the neuronal dopaminergic system as systemic administration of nicotine decreased [(11)C]raclopride binding in the anesthetized state. Since high doses of systemically administered nicotine are harmful, we administrated it directly into the rat striatum via microdialysis. We then examined the acute effects of continuous central administration of high doses of nicotine on striatal dopamine concentrations by measuring [(11)C]raclopride binding by positron emission tomography. The concentration of dopamine in the dialysates was significantly increased from basal levels when microdialysis with 100 mM nicotine was initiated. However, contrary to expectations, the binding potential (BP) of [(11)C]raclopride in the nicotine-perfused striatum was significantly higher than that in control striatum. Preinjection of mecamylamine (3 mg/kg), a nicotinic antagonist, had no effect on either extracellular dopamine levels or on the BP of [(11)C]raclopride. These findings suggest that the high dose of local nicotine administration induced mecamylamine-insensitive local increases in extracellular dopamine, but might have decreased the total amount of extracellular dopamine in the striatum.