Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases.

PURPOSE: Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([18F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [18F]FSW-100. METHODS: Process validation of [18F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [18F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans. RESULTS: Three consecutive validation runs of the automated radiosynthesis gave [18F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [18F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [18F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific. CONCLUSION: These results support the clinical utility of [18F]FSW-100 for in vivo imaging of HDAC6 in the brain.

Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

High performance plasma amyloid-ß biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-ß deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-ß positron-emission tomography (PET) imaging or measurement of amyloid-ß in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-ß markers. Here we demonstrate the measurement of high-performance plasma amyloid-ß biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-ß precursor protein (APP)669-711/amyloid-ß (Aß)1-42 and Aß1-40/Aß1-42 ratios, and their composites, to predict individual brain amyloid-ß-positive or -negative status was determined by amyloid-ß-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-ß burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-ß-PET burden and levels of Aß1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-ß burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

T2-FLAIR mismatch sign correlates with 11C-methionine uptake in lower-grade diffuse gliomas.

PURPOSE: The T2-FLAIR mismatch sign is recognized as an imaging finding highly suggestive of IDH-mutant astrocytomas. This study was designed to determine whether the T2-FLAIR mismatch sign correlates with uptake of 11C-methionine in lower-grade gliomas. METHODS: We included 78 histopathologically verified lower-grade gliomas (grade 2: 31 cases, grade 3: 47 cases) in this study. 78 patients underwent 11C-methionine positron emission tomography (MET-PET) scans and magnetic resonance (MR) imaging scans prior to histological diagnosis. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. MR imaging scans were evaluated for the presence of the T2-FLAIR mismatch sign by three independent reviewers. We compared molecular status, the T2-FLAIR mismatch sign and 11C-methionine uptake among patients with different lower-grade glioma molecular types. RESULTS: The 78 lower-grade gliomas were assigned to one of three molecular groups: Group A (IDH-mutant and 1p/19q non-codeleted, n = 22), Group O (IDH-mutant and 1p/19q codeleted, n = 20), and Group W (IDH wildtype, n = 36). T2-FLAIR mismatch was found in 16 cases (20.5%) that were comprised of 8 (36.4%), 0 (0%), 8 (22.2%) cases in the molecular group A, O and W, respectively. The median T/N ratio of MET-PET in tumors with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.83, p < 0.001, Mann-Whitney U test). In the Groups A and W (excluding Group O), the median T/N ratio on MET-PET in groups A and W (but not group O) with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.81, p = 0.002, Mann-Whitney U test). CONCLUSION: The T2-FLAIR mismatch sign correlated with lower 11C-methionine uptake in lower grade gliomas.

Differences in cerebral blood flow measurement using arterial spin labeling MRI between patients with moyamoya disease and patients with arteriosclerotic cerebrovascular disease.

BACKGROUND: It is unclear whether the accuracy of arterial spin labeling (ASL) magnetic resonance imaging (MRI) is the same between moyamoya disease (MMD), which is known to have markedly elevated cerebral blood volume (CBV), and atherosclerotic intracranial arterial stenosis (AS), which has relatively less elevated CBV. PURPOSE: To investigate how the differences in hemodynamics affect measurement of ASL-cerebral blood flow (CBF) using ASL for patients with MMD and AS. MATERIAL AND METHODS: Fourteen MMD and ten AS patients were evaluated with ASL-MRI, magnetic resonance angiography (MRA), and 15O-gas positron emission computed tomography (PET). The regional CBF values of ASL using two post-labeling delays (PLDs; 1525 ms and 2525 ms) were compared with the PET-derived CBF, CBV, and mean transit time (MTT). Corresponding anterior circulation results were evaluated by flow territory map-based analysis. RESULTS: The correlation between the ASL-CBF values (2525 ms) and PET-CBF declined in the MMD group (r = 0.28; P < 0.01), while the AS group showed good correlation (r = 0.77; P < 0.01). In the MMD group, the ASL-CBF values (2525 ms) overestimated the PET-CBF values as the regional CBV values increased (r = 0.35; P < 0.01). When the regions of interest were divided into two subgroups according to the degree of arterial stenosis by MRA, the correlation coefficient between the ASL-CBF (2525 ms) and PET-CBF values improved (mild stenosis: r = 0.36; P = 0.06; severe stenosis: r = 0.51; P < 0.01). CONCLUSION: The accuracy of CBF measurements using ASL-MRI differed between patients with MMD and AS. The prominent increase of CBV and the degree of arterial stenosis may have affected the accuracy of ASL-CBF in patients with MMD.

Adenosine A2A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease.

BACKGROUND: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2A R) antagonist action. OBJECTIVE: We aimed to calculate occupancy rates of striatal A2A Rs by caffeine after coffee intake in PD. METHODS: Five patients with PD underwent 11 C-preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. RESULTS: The mean serum caffeine level (µg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2A Rs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. CONCLUSIONS: A sufficient A2A R occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spatial coefficient of variation of arterial spin labeling MRI for detecting hemodynamic disturbances measured with 15O-gas PET in patients with moyamoya disease.

PURPOSE: The aim of this study was to investigate whether the spatial coefficient of variation of arterial spin labeling (ASL-CoV) acquired in clinical settings can be used to estimate the hemodynamic disturbances measured with 15O-gas positron emission tomography (PET), especially an increased oxygen extraction fraction (OEF), in patients with moyamoya disease. METHODS: We evaluated 68 adult patients with moyamoya disease who underwent ASL (postlabeling delay (PLD) = 1525 ms and 2525 ms) and PET. Regional values were measured using the middle cerebral artery territorial atlas divided into proximal, middle, and distal regions based on the arterial transit time, and correlations of ASL-CoV with cerebral blood flow, cerebral blood volume, mean transit time, and OEF, as well as the relationship between increased OEF and ASL-CoV, were evaluated. RESULTS: Regardless of the choice of region and PLD, ASL-CoV was significantly correlated with PET-measured parameters, including OEF (|ρ|= 0.30-0.80, P < 0.001). Regions with an increased OEF showed a significantly higher ASL-CoV than regions with a nonincreased OEF (P ≤ 0.03) regardless of the choice of region and PLD. The accuracy of identification of an increased OEF was highest when using a PLD of 1525 ms and the middle region (area under the curve = 0.750; using a cutoff value of 31.27, sensitivity = 97.4%, specificity = 41.7%, negative predictive value = 92.6%, and positive predictive value = 67.9%). CONCLUSION: ASL-CoV may help identify patients with increased OEF.

[Clinical Findings of Thalamic and Brainstem Glioma Including Diffuse Midline Glioma, H3K27M Mutant:A Clinical Study].

BACKGROUND: Diffuse midline glioma, H3K27M mutant is a glioma located in the thalamus, brainstem, or spine with the H3K27M mutation, which is a new entity in the 2016 revised WHO classification. The treatment of thalamic glioma(TG)and brainstem glioma(BSG), which includes diffuse midline gliomas, the H3K27M mutant is challenging, and there are no standard therapeutic strategies. It is important to determine the characteristics of these brain tumors. Here, we retrospectively reviewed 31 consecutive patients with TG and BSG who were treated at our institute between January 1994 and May 2018, including methionine-positron emission tomography(MET-PET)data. RESULTS: Fourteen patients had TG, while 17 patients had BSG. Six patients were children, and 25 were adults. Nine patients with TGs and seven with BSG were enhanced by gadolinium. Twenty-seven patients were treated with radiotherapy, and 20 patients were treated with chemotherapy. All 21 tumors that underwent surgery showed wild-type IDH. The H3K27M mutation was present in four TG and two BSG. There was no statistically significant association between methionine uptake and gadolinium contrast enhancement and tumor grade. The median overall survival period(OS)of all cases was 16.9 months, whereas those of TG and BSG were 22.8 and 10.0 months, respectively. CONCLUSION: Because TG and BSG still have poor prognoses, it is necessary to elucidate the pathology of the disease and establish its standard therapy.

[Cross-validation of Quantitative Analytical Software Using 18F-florbetapir PET Imaging].

BACKGROUND: 18F-florbetapir is an amyloid ß (Aß) -targeted 18F-labeled positron emission tomography (PET) tracer for the clinical diagnosis of Alzheimer's disease. The standardized uptake value ratio (SUVR) serves as a tool with which to differentially diagnose. The present study aimed to cross-validate and compare SUVR derived from Amygo neuro and MIMneuro software. METHODS: We injected 40 individuals with 18F-florbetapir and then acquired PET images from 50 to 60 minutes later. All images were separately normalized to the standard 18F-florbetapir PET template using Amygo neuro and MIMneuro. Volumes of interest (VOIs) were automatically placed on six target regions each in Amygo neuro and MIMneuro. The composite SUVR (cSUVR) and regional SUVR (rSUVR) were calculated from mean values measured in VOI. A cSUVR of>1.10 was defined as representing Aß positivity. Correlation coefficients were calculated in the two types of software. RESULTS: A cSUVR>1.10 was determined by Amygo neuro and MIMneuro in 15 of the 40 individuals. The rSUVR in the posterior cingulate, parietal lobe, precuneus, and temporal lobe significantly differed between Amygo neuro and MIMneuro, whereas the cSUVR did not. The SUVR calculated by the two types of software closely correlated to each other (R=0.89-0.96, P<0.05). CONCLUSIONS: The cSUVR was not different between Amygo neuro and MIMneuro. We suggest that Amygo neuro is comparable to MIMneuro in quantitative analysis using SUVR for 18F-florbetapir imaging, thus facilitating the use of standardized quantitative approaches to amyloid PET imaging.

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography.

BACKGROUND: 18F-THK5351 was recently shown to bind to monoamine oxidase B (MAO-B) with high affinity. MAO-B is highly concentrated in astrocytes and increases during astrogliosis. Therefore, 18F-THK5351 accumulates in lesions undergoing astrogliosis. Cerebral infarction causes astrogliosis, which may be beneficial for repairing and regenerating injured cells and tissues in the lesions. Therefore, monitoring the degree of astrogliosis and stroke symptoms is essential for understanding the roles of astrogliosis in cerebral infarction. CASE PRESENTATION: A 72-year-old man, complaining of total loss of sensation in the left index finger, was diagnosed with acute cerebral infarction, and underwent 18F-THK5351 positron emission tomography (PET) on two occasions after the stroke. The first PET scan performed on day 27 revealed intense uptake in the infarct lesion located around the right precentral and postcentral gyri. However, the second PET scan on day 391 showed that the uptake had diminished significantly. The sensory deficit in the left index finger had improved by 30 and 70% at the times of the first and second PET scans, respectively. CONCLUSIONS: 18F-THK5351 uptake in the infarct lesion evidently changed between days 27 and 391, along with improved sensory deficit in the left index finger. Astrocytes reportedly play a role in restoring neuronal integrity. Therefore, the temporal course of astrogliosis may have been related to improving stroke symptoms in this patient, suggesting that the degree of astrogliosis in the infarct lesion may aid in assessing the prognosis in stroke patients.

Neural substrate of a cognitive intervention program using Go game: a positron emission tomography study.

BACKGROUND: Influence of cognitive intervention programs on brain activity has not been enough explored. AIMS: The aims of the present study were to clarify changes in brain activity from a cognitive intervention program utilizing the board game "Go" and to examine the relationship between brain activity and the acquisition of Go skills. METHODS: Eighteen community-dwelling older adults were randomly assigned either to an intervention group (IG), in which members attended 12 Go lessons either in groups or individually using tablet computers, or a control group (CG), in which members attended health education lectures unrelated to Go. Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), cognitive assessments, and Go tests were performed before and after the intervention. RESULTS: The results showed different patterns of regional FDG uptake in both groups: regional cerebral glucose metabolism was significantly increased in the left middle temporal gyrus (MTG) and bilateral putamen (p < 0.01; cluster level) in the IG, and in the left superior frontal gyrus in the CG, (p < 0.01; cluster level). Furthermore, Go test scores were significantly improved in the IG (p < 0.05), and a significant association was observed between changes in Go test scores and glucose metabolism in the left MTG (p < 0.05). CONCLUSIONS AND DISCUSSION: This study indicates that a cognitive intervention program using Go may enhance brain activity. Further studies with larger populations and longer observation periods are needed to clarify the neural mechanisms underlying our Go intervention program.

Magnetic resonance-guided focused ultrasound ablation of hypothalamic hamartoma as a disconnection surgery: a case report.

We report the case of a patient with hypothalamic hamartoma (HH) who was successfully treated with magnetic resonance-guided focused ultrasound (MRgFUS) for ablation as a disconnection surgery. A 26-year-old man with gelastic epilepsy had been diagnosed with HH at 3 years of age, and antiepileptic drugs were administered due to worsening episodes. Magnetic resonance imaging showed a sessile parahypothalamic hamartoma and MRgFUS ablation was performed, creating an oval-shaped lesion at the boundary area of the HH. Dramatic improvements in seizure symptoms were noted, and he was seizure-free on decreased antiepileptic drugs without any adverse events over the 1-year follow-up period.

Radiosynthesis and preliminary evaluation of an 18 F-labeled tubastatin A analog for PET imaging of histone deacetylase 6.

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18-labeled ligand [18 F]3, which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18 F]3 was synthesized by a two-step reaction composed of 18 F-fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18 F]3. Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18 F]3, suggesting low brain uptake of [18 F]3 was not caused by the P-glycoprotein-mediated efflux. While PET imaging using [18 F]3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.

Unraveling Specific Brain Microstructural Damage in Moyamoya Disease Using Diffusion Magnetic Resonance Imaging and Positron Emission Tomography.

BACKGROUND AND PURPOSE: Chronic ischemia may induce brain microstructural damage and lead to neurocognitive dysfunction in patients with Moyamoya disease (MMD). We applied neurite orientation dispersion and density imaging (NODDI) and 15O-gas positron emission tomography (PET) to elucidate the specific ischemic brain microstructural damage of MMD in the cortex and the white matter. MATERIALS AND METHODS: Thirty-one patients (16-63years old, 9 males) and 20 age- and sex-matched normal controls were enrolled in this study. NODDI evaluates quantitative parameters reflecting neurite and axonal density, network complexity and the interstitial fluid in all participants. Of 31 patients, 12 newly diagnosed patients were evaluated with PET, also. We evaluated correlations between the microstructural parameters of NODDI and the hemodynamic and metabolic parameters of PET, the relationship between NODDI and clinical severity of each hemisphere (Normal, Asymtpomatic, Symptomatic, and Infarcted) as well as neurocognitive performance. RESULTS: All NODDI parameters significantly correlated with PET parameters (absolute r = 0.46-0.83, P ≤ .048) and clinical severity (P < .001), suggesting that neurite and axonal density and network complexity decreased, and the interstitial fluid increased, as the ischemic burden became severe. NODDI parameters reflecting neurite and axonal density and network complexity significantly correlated with neurocognitive profiles (r = 0.36-0.64, P ≤ .048), but the interstitial fluid component did not. CONCLUSIONS: Chronic ischemia in patients with MMD may induce decreased neurite and axonal density, simplified network complexity, and may lead to neurocognitive dysfunction. The increased interstitial fluid accompanying hemodynamic impairment may not be identical to the decreased neurite density and might be driven by another mechanism.

Altered functional connectivity of the default mode network by glucose loading in young, healthy participants.

BACKGROUND: The functional connectivity of the default mode network (DMN) decreases in patients with Alzheimer's disease (AD) as well as in patients with type 2 diabetes mellitus (T2DM). Altered functional connectivity of the DMN is associated with cognitive impairment. T2DM is a known cause of cognitive dysfunction and dementia in the elderly, and studies have established that T2DM is a risk factor for AD. In addition, recent studies with positron emission tomography demonstrated that increased plasma glucose levels decrease neuronal activity, especially in the precuneus/posterior cingulate cortex (PC/PCC), which is the functional core of the DMN. These findings prompt the question of how increased plasma glucose levels decrease neuronal activity in the PC/PCC. Given the association among DMN, AD, and T2DM, we hypothesized that increased plasma glucose levels decrease the DMN functional connectivity, thus possibly reducing PC/PCC neuronal activity. We conducted this study to test this hypothesis. RESULTS: Twelve young, healthy participants without T2DM and insulin resistance were enrolled in this study. Each participant underwent resting-state functional magnetic resonance imaging in both fasting and glucose loading conditions to evaluate the DMN functional connectivity. The results showed that the DMN functional connectivity in the PC/PCC was significantly lower in the glucose loading condition than in the fasting condition (P = 0.014). CONCLUSIONS: Together with previous findings, the present results suggest that decreased functional connectivity of the DMN is possibly responsible for reduced PC/PCC neuronal activity in healthy individuals with increased plasma glucose levels.

Preventive effects of an intergenerational program on age-related hippocampal atrophy in older adults: The REPRINTS study.

OBJECTIVES: A growing body of literature indicates that social engagements, such as intergenerational programs, are effective strategies to improve a range of cognitive abilities. The present study examined whether the intergenerational program-REPRINTS-prevents age-related hippocampal atrophy. METHODS: After comprehensive baseline assessment, participants were allowed to decide whether to participate in the REPRINTS intervention or in the control group, which required only completion of assessments. REPRINTS participants engaged in group activities that involved reading picture books to children at kindergarten and elementary schools, once every 1 to 2 weeks. A follow-up assessment was conducted after 6 years. Two MRI scans were performed, one immediately after baseline assessment and the other after 6 years. Volumes of the hippocampus, thalamus, and caudate nucleus were derived from automated segmentation. The analysis included 17 REPRINTS and 42 control-group participants. RESULTS: There was no significant difference in any variable of participants' characteristics at baseline between the REPRINTS and control groups. Hippocampal volume significantly declined in the control group but was maintained in the REPRINTS group. No significant differences between groups in thalamus or caudate nucleus volume were observed. Although cognitive function was unaffected by the program, greater decreases in hippocampal volume were significantly correlated with greater decreases in cognitive performance scores. CONCLUSIONS: Our results suggest that the REPRINTS intergenerational program has protective effects on age-related hippocampal atrophy in older adults. These changes precede improvements in cognitive performance, suggesting the validity of the concept of brain plasticity in later life following social engagement.

Dynamic Exercise Elicits Dissociated Changes Between Tissue Oxygenation and Cerebral Blood Flow in the Prefrontal Cortex: A Study Using NIRS and PET.

Neuronal activity causes changes in both cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF). Since the relationship between tissue oxygenation and regional CBF (rCBF) during exercise has not been elucidated, we compared the data obtained using near-infrared spectroscopy (NIRS) and rCBF examined using positron emission tomography (PET). Participants in this study comprised 26 healthy young men. Changes in concentration of oxygenated hemoglobin (ΔO2Hb) and deoxygenated hemoglobin (ΔHHb) in the prefrontal cortex (PFC) were measured using NIRS continuously during a 15-min bout of the constant-load low-intensity cycling exercise (n = 14). Under the same protocol as the NIRS study, rCBF was measured using H215O and PET by the autoradiographic method at baseline (Rest) and at 3 min (Ex1) and 13 min (Ex2) after starting exercise (n = 12). As systematic factors influenced by exercise, heart rate, end-tidal pressure of carbon dioxide (PETCO2) and blood pressure (BP) were monitored. For each region investigated by NIRS, rCBF was analyzed quantitatively using PET-MRI co-registered standardized images. Despite inter-individual differences, changing patterns of ΔO2Hb and ΔHHb in the PFC were similar between channels. Significant main effects for time point were identified in ΔO2Hb, ΔHHb and changes in rCBF. While rCBF increased from rest, ΔO2Hb was not changed at Ex1. Conversely, rCBF was unchanged from rest but ΔO2Hb was significantly increased at Ex2. Fluctuations of PETCO2 and BP evoked by exercise were not in accordance with changes in ΔO2Hb, ΔHHb and rCBF, while BP may affect the forehead skin blood flow. Given that NIRS data are a mixture of skin and brain effects, our results suggest that CMRO2 may differ between the phases in a bout of dynamic exercise. The present study indicates the utility of NIRS to examine the relationship between CMRO2 and rCBF during exercise.

Response of Cerebral Blood Flow and Blood Pressure to Dynamic Exercise: A Study Using PET.

Dynamic exercise elicits fluctuations in blood pressure (BP) and cerebral blood flow (CBF). This study investigated responses in BP and CBF during cycling exercise and post-exercise hypotension (PEH) using positron emission tomography (PET). CBF was measured using oxygen-15-labeled water (H215O) and PET in 11 human subjects at rest (Rest), at the onset of exercise (Ex1), later in the exercise (Ex2), and during PEH. Global CBF significantly increased by 13% at Ex1 compared with Rest, but was unchanged at Ex2 and during PEH. Compared with at Rest, regional CBF (rCBF) increased at Ex1 (20~42%) in the cerebellar vermis, sensorimotor cortex for the bilateral legs (M1Leg and S1Leg), insular cortex and brain stem, but increased at Ex2 (28~31%) only in the vermis and M1Leg and S1Leg. During PEH, rCBF decreased compared with Rest (8~13%) in the cerebellum, temporal gyrus, piriform lobe, thalamus and pons. The areas showing correlations between rCBF and mean BP during exercise and PEH were consistent with the central autonomic network, including the brain stem, cerebellum, and hypothalamus (R2=0.25-0.64). The present study suggests that higher brain regions are coordinated through reflex centers in the brain stem in order to regulate the cardiovascular response to exercise.

Japanese and North American Alzheimer's Disease Neuroimaging Initiative studies: Harmonization for international trials.

INTRODUCTION: We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America. METHODS: A total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid ß(1-42)-positive LMCI and mild AD between J-ADNI and ADNI. RESULTS: Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230). DISCUSSION: These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries.

Unique Angiographic Appearances of Moyamoya Disease Detected with 3-Dimensional Rotational Digital Subtraction Angiography Imaging Showing the Hemodynamic Status.

BACKGROUND: The aim of this study was to identify the unique morphological arterial features in patients with moyamoya disease on 3-dimensional rotational digital subtraction angiography. MATERIALS AND METHODS: One hundred seven hemispheres of 58 consecutive patients with moyamoya disease that were analyzed with fused 3-dimensional images of internal carotid angiograms and vertebral angiograms that were marked with different colors were reviewed. Angiographic findings in the posterior watershed area were classified, and the utility of the classification was analyzed by comparing it with clinical presentations and quantitative hemodynamic parameters obtained with positron emission tomography. RESULTS: Two unique angiographic appearances were identified. A vacant vessel appearance (no arterial inflow despite absence of cortical infarction) was observed mostly in transient ischemic attack hemispheres. In hemispheres with a vacant vessel appearance, cerebral blood flow was decreased, cerebral blood volume was increased, and mean transit time was prolonged significantly (P = .00017, P = .0061, and P = .00026, respectively). A cocktail vessel appearance (mixture of carotid and vertebral arterial flow) was most commonly observed in asymptomatic cases, as well as in ischemic hemispheres. Cerebral blood volume increased and mean transit time was prolonged significantly (P = .036 and P = .014, respectively) in hemispheres with a cocktail vessel appearance. The trend of progression in hemodynamic severity in the order of normal appearance, cocktail vessel appearance, and vacant vessel appearance in the watershed area was statistically significant. CONCLUSION: Fused 3-dimensional digital subtraction angiography demonstrated unique angiographic features in the watershed area, and this represented the degree of cerebral hemodynamic impairment in moyamoya disease.