Multimodal imaging analyses in neuromyelitis optica spectrum disorder with or without visual disturbance.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder is a demyelinating and inflammatory affliction that often leads to visual disturbance. Various imaging techniques, including free-water imaging, have been used to determine neuroinflammation and degeneration. Therefore, this study aimed at determining multimodal imaging differences between patients with neuromyelitis optica spectrum disorder, especially those with visual disturbance, and healthy controls. MATERIALS AND METHODS: Eighty-five neuromyelitis optica spectrum disorder patients and 89 age- and sex-matched healthy controls underwent 3-T magnetic resonance imaging (MRI). We analyzed adjusted brain-predicted age difference, voxel-based morphometry, and free-water-corrected diffusion tensor imaging (DTI) by tract-based spatial statistics in each patient group (MRI-positive/negative neuromyelitis optica spectrum disorder patients with or without a history of visual disturbance) compared with the healthy control group. RESULTS: MRI-positive neuromyelitis optica spectrum disorder patients exhibited reduced volumes of the bilateral thalamus. Tract-based spatial statistics showed diffuse white matter abnormalities in all DTI metrics in MRI-positive neuromyelitis optica spectrum disorder patients with a history of visual disturbance. In MRI-negative neuromyelitis optica spectrum disorder patients with a history of visual disturbance, voxel-based morphometry showed volume reduction of bilateral thalami and optic radiations, and tract-based spatial statistics revealed significantly lower free-water-corrected fractional anisotropy and higher mean diffusivity in the posterior dominant distributions, including the optic nerve radiation. CONCLUSION: Free-water-corrected DTI and voxel-based morphometry analyses may reflect symptoms of visual disturbance in neuromyelitis optica spectrum disorder.

Assessment of Gray Matter Microstructural Alterations in Alzheimer's Disease by Free Water Imaging.

Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

MRI detection of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) on T1WI-CHESS.

Mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) is a recently proposed epileptogenic entity that is difficult to detect on MRI. We present a case of MOGHE that was successfully detected on T1WI-chemical shift-selective saturation (CHESS) MRI. The clinical presentation, MRI including T1WI-CHESS, functional images, and pathology findings of a 14-year-old Japanese girl diagnosed with MOGHE are described. T1WI-CHESS revealed an abnormal high signal along the affected lesion, whereas the findings shown by the other MR sequences were less obvious; interictal fluorodeoxyglucose-positron emission tomography indicated slightly decreased accumulation in the lesion, and subtraction ictal single photon emission computed tomography co-registered to MRI showed an increased blood flow. Together these observations suggest that T1WI-CHESS may be a useful MR sequence for detecting the lesions in patients with MOGHE.

CD11chigh B Cell Expansion Is Associated With Severity and Brain Atrophy in Neuromyelitis Optica.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica (NMO) is an autoimmune astrocytopathy mediated by anti-AQP4 antibody-producing B cells. Recently, a B-cell subset highly expressing CD11c and T-bet, originally identified as age-associated B cells, has been shown to be involved in the pathogenesis of various autoimmune diseases. The objective of this study was to determine the relationship between the frequency of CD11chigh B cells per CD19+ B cells in the peripheral blood of patients with NMO and the clinical profiles including the brain volume. METHODS: In this observational study, 45 patients with anti-AQP4 antibody-positive NMO in remission and 30 healthy control subjects (HCs) were enrolled. Freshly isolated peripheral blood mononuclear cells were analyzed for immune cell phenotypes. The frequency of CD11chigh B cells per CD19+ B cells was assessed by flow cytometry and was evaluated in association with the clinical profiles of patients. Brain MRI data from 26 patients were included in the study for the analysis on the correlation between CD11chigh B-cell frequency and brain atrophy. RESULTS: We found that the frequency of CD11chigh B cells in CD19+ B cells was significantly increased in patients with NMO compared with HCs. The expansion of CD11chigh B cells significantly correlated with EDSS, past relapse numbers, and disease duration. In addition, a higher frequency of CD11chigh B cells negatively correlated with total brain, white matter, and gray matter volumes and positively correlated with T2/FLAIR high lesion volumes. When the past clinical relapse episodes of patients with or without the expansion of CD11chigh B cells were compared, relapses in the brain occurred more frequently in patients with CD11chigh B-cell expansion. CD11chigh B cells had distinct features including expression of chemokine receptors associated with migration into peripheral inflammatory tissues and antigen presentation. CD11chigh B-cell frequency was positively correlated with T peripheral helper-1 (Tph-1) cell frequency. DISCUSSION: Even during the relapse-free period, CD11chigh B cells could expand in the long disease context, possibly through the interaction with Tph-1 cells. The increased frequency of CD11chigh B cells associated with brain atrophy and disease severity, indicating that this cell population could be involved in chronic neuroinflammation in NMO.

Glymphatic System Activity and Brain Morphology in Patients With Psychogenic Non-epileptic Seizures.

BACKGROUND: To clarify the neural correlates underlying psychogenic non-epileptic seizures (PNES), we compared glymphatic system activity between patients with PNES and healthy participants using diffusion tensor imaging (DTI)-analysis along the perivascular space (ALPS) method. METHODS: The DTI scans were acquired from 16 patients with PNES and 25 healthy participants. We computed the DTI-ALPS index as an index of glymphatic system function and estimated the disease-related changes in the DTI-ALPS index and brain structures in PNES patients. RESULTS: There were no significant differences in the DTI-ALPS index between patients with PNES and healthy participants. On the other hand, patients with PNES had decreased fractional anisotropy values in the bilateral posterior cingula, a higher mean diffusivity value around the left insula, and a lower gray matter volume in the bilateral amygdalae compared with healthy participants. CONCLUSIONS: Patients with PNES exhibited an impairment of white matter integrity and a reduction of gray matter volume, but no glymphatic-system changes. These findings will play a significant role in our comprehension of this complex illness.

Comparison of 3D Magnetization-transfer- and Spectral-presaturation-with-inversion-recovery-based Neuromelanin Imaging.

PURPOSE: Neuromelanin is visualized by optimizing the conditions of longitudinal relaxation (T1)-weighted imaging (T1WI). Although it was originally developed in 2D imaging, 3D imaging has been also reported, and T1WI sequences with magnetization transfer (MT) pulses are now widely used in 3D gradient echo (GRE) sequences. In this study, we assert that the use of spectral presaturation with inversion recovery (SPIR) may also be useful as an alternative to MT pulses, and we optimize SPIR and compare it with MT. METHODS: Neuromelanin images with MT pulse and SPIR (flip angles [FAs] = 19º, 22º, and 25º) were acquired from 30 healthy volunteers. To achieve the same acquisition time of 5 min, the slab thickness of the MT images was less than 1/3 of those of the SPIR images; the acquisition areas for MT and SPIR were the brainstem and the whole brain, respectively. Visual and quantitative evaluation was performed and compared on the four sequences acquired for the substantia nigra pars compacta (SNc) and the locus coeruleus (LC). For visual assessment, we used the mean score from a 3-point scale by two evaluators. For quantitative evaluation, the contrast ratios of SNc and LC were calculated in comparison with the background tissue signal. RESULTS: In visual assessments, the mean scores of the SPIR FA19º and FA22º images were better than others in the SNc. Regarding LC, the SPIR FA22º image yielded the best mean score. In quantitative evaluations, the MT image was significantly lower than the other three images in SNc. Regarding LC, there were no significant differences among the four acquired images (MT and SPIR FA19º, FA22º, and FA25º). CONCLUSIONS: Detection of neuromelanin in SNc and LC was improved by the use of SPIR compared to MT pulse in 3D neuromelanin imaging.

Brain Abnormalities in Becker Muscular Dystrophy: Evaluation by Voxel-Based DTI and Morphometric Analysis.

BACKGROUND AND PURPOSE: Although various neuropsychological problems in Becker muscular dystrophy have attracted attention, there have been few related neuroimaging studies. We investigated brain abnormalities in patients with Becker muscular dystrophy using 3D T1WI and DTI. MATERIALS AND METHODS: MR images were obtained for 30 male patients and 30 age-matched healthy male controls. We classified patients into Dp140+ and Dp140- subgroups based on their predicted dystrophin Dp140 isoform expression and performed voxel-based comparisons of gray and white matter volumes and DTI metrics among the patients, patient subgroups, and controls. ROI-based DTI analyses were also performed. RESULTS: Significantly decreased fractional anisotropy was observed in the left planum temporale and right superior parietal lobule compared between the Becker muscular dystrophy and control groups. In the Dp140- subgroup, decreased fractional anisotropy was observed in the left planum temporale, but no significant changes were seen in the Dp140+ subgroup. The ROI-based analysis obtained the same results. No significant differences were evident in the gray or white matter volumes or the DTI metrics other than fractional anisotropy between the groups. CONCLUSIONS: A DTI metric analysis is useful to detect white-matter microstructural abnormalities in Becker muscular dystrophy that may be affected by the Dp140 isoform expression.

Brain structural changes in alternating hemiplegia of childhood using single-case voxel-based morphometry analysis.

BACKGROUND AND PURPOSE: Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by ATP1A3 mutations. Using voxel-based morphometry (VBM) analysis, we compared an AHC patient cohort with controls. Additionally, with single-case VBM analysis, we assessed the associations between clinical severity and brain volume in patients with AHC. MATERIALS AND METHODS: To investigate structural brain changes in gray matter (GM) and white matter (WM) volumes between 9 patients with AHC and 20 age-matched controls, VBM analysis was performed using three-dimensional T1-weighted magnetic resonance imaging. Single-case VBM analysis was also performed on nine patients with AHC to investigate the associations between the respective volumes of GM/WM differences and the motor level, cognitive level, and status epilepticus severity in patients with AHC. RESULTS: Compared with controls, patients with AHC showed significant GM volume reductions in both hippocampi and diffuse cerebellum, and there were WM reductions in both cerebral hemispheres. In patients with AHC, cases with more motor dysfunction, the less GM/WM volume of cerebellum was shown. Three of the six cases with cognitive dysfunction showed a clear GM volume reduction in the insulae. Five of the six cases with status epilepticus showed the GM volume reduction in hippocampi. One case had severe status epilepticus without motor dysfunction and showed no cerebellar atrophy. CONCLUSION: With single-case VBM analysis, we could show the association between region-specific changes in brain volume and the severity of various clinical symptoms even in a small sample of subjects.

Double inversion recovery MRI of subcortical band heterotopia and its variations.

BACKGROUND AND PURPOSE: Subcortical band heterotopia (SBH) is a malformation of cortical development diagnosed via MRI. Currently, patients with SBH are classified according to Di Donato's classification. We aimed to show a variation of SBH and the usefulness of double inversion recovery (DIR) images. METHODS: We retrospectively reviewed the MRI findings of 28 patients with SBH. The patients were classified according to Donato's classification by using conventional MR images, and their DIR findings were reviewed. RESULTS: Of 28 patients, 20 were grade 1 and 8 were grade 2 according to Di Donato's classification. In 15 of 28 patients, the following four types of atypical MRI findings were detected: asymmetry distribution (four cases), coexistence of thin and thick SBH (five cases), and DIR faint abnormal signal intensity in subcortical white matter (five cases) and in deep white matter (five cases). The latter two types were detected on DIR alone and have not been reported. Additionally, these were identified only in the mild group (Di Donato's classification 1-1 or 1-2). CONCLUSION: DIR is a useful MRI sequence for detecting faint white matter signal abnormalities, and it can aid in the accurate classification of SBH and identification of its variations, which may reflect the pathology of SBH.

Relationship between the tau protein and choroid plexus volume in Alzheimer's disease.

Tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent studies found that the choroid plexus (CP) has a role in ß-amyloid and tau protein clearance in the brain. We evaluated the relationships between CP volume and the ß-amyloid and tau protein depositions. Participants were 20 patients with AD and 35 healthy subjects who underwent MRI and PET scanning using the ß-amyloid tracer 11C-PiB and the tau/inflammatory tracer 18F-THK5351. We computed the volume of the CP and estimated the relationships between the CP volume and ß-amyloid and tau protein/inflammatory deposition by Spearman's correlation test. The CP volume was significantly positively correlated with both the standardized uptake value ratio (SUVR) of 11C-PiB and the SUVR of 18F-THK5351 in all participants. The CP volume was also significantly positively correlated with the SUVR of 18F-THK5351in patients with AD. Our data suggested that the volume of the CP was a good biomarker for the evaluation of tau deposition and neuroinflammation.

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND AND PURPOSE: Free-water-corrected diffusion tensor imaging (FW-DTI), a new analysis method for diffusion MRI, can indicate neuroinflammation and degeneration. There is increasing evidence of autoimmune etiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We used FW-DTI and conventional DTI to investigate microstructural brain changes related to autoantibody titers in patients with ME/CFS. METHODS: We prospectively examined 58 consecutive right-handed ME/CFS patients who underwent both brain MRI including FW-DTI and a blood analysis of autoantibody titers against ß1 adrenergic receptor (ß1 AdR-Ab), ß2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. We investigated the correlations between these four autoantibody titers and three FW-DTI indices-free water (FW), FW-corrected fractional anisotropy (FAt), and FW-corrected mean diffusivity-as well as two conventional DTI indices-fractional anisotropy (FA) and mean diffusivity. The patients' age and gender were considered as nuisance covariates. We also evaluated the correlations between the FW-DTI indices and the performance status and disease duration. RESULTS: Significant negative correlations between the serum levels of several autoantibody titers and DTI indices were identified, mainly in the right frontal operculum. The disease duration showed significant negative correlations with both FAt and FA in the right frontal operculum. The changes in the FW-corrected DTI indices were observed over a wider extent compared to the conventional DTI indices. CONCLUSIONS: These results demonstrate the value of using DTI to assess the microstructure of ME/CFS. The abnormalities of right frontal operculum may be a diagnostic marker for ME/CFS.

First-in-human clinical trial of the NKT cell-stimulatory glycolipid OCH in multiple sclerosis.

Background: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes the damage to the myelin sheath as well as axonal degeneration. Individuals with MS appear to have changes in the numbers and functions of T-cell subsets, leading to an immunological imbalance accompanied by enhanced autoreactivity. In previous preclinical studies, (2 S,3 S,4R)-1-O-(α-D-Galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a synthetic analog of α-galactosylceramide stimulatory for invariant NKT (iNKT) cells, has shown therapeutic or disease-preventive immunoregulatory effects in autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE). Objectives: This study is the first-in-human study of oral OCH to evaluate the pharmacokinetics and to examine the effects on immune cells as well as related gene expression profiles. Methods: Fifteen healthy volunteers and 13 MS patients who met the study criteria were enrolled. They were divided into five cohorts and received oral administration of various doses of granulated powder of OCH (0.3-30 mg), once per week for 4 or 13 weeks. Plasma OCH concentrations were measured by high-performance liquid chromatography. Frequencies of lymphocyte subsets in peripheral blood were evaluated by flow cytometry, and microarray analysis was performed to determine OCH-induced changes in gene expression. Results: Oral OCH was well tolerated, and its bioavailability was found to be sufficient. Six hours after a single dose of OCH, increased frequencies of Foxp3+ regulatory T-cells were observed in some cohorts of healthy subjects and MS patients. Furthermore, gene expression analysis demonstrated an upregulation of several immunoregulatory genes and downregulation of pro-inflammatory genes following OCH administration. Conclusion: This study has demonstrated immunomodulatory effects of the iNKT cell-stimulatory drug OCH in human. Safety profiles together with the presumed anti-inflammatory effects of oral OCH encouraged us to conduct a phase II trial.

Age and Sex-Related Effects on Single-Subject Gray Matter Networks in Healthy Participants.

Recent developments in image analysis have enabled an individual's brain network to be evaluated and brain age to be predicted from gray matter images. Our study aimed to investigate the effects of age and sex on single-subject gray matter networks using a large sample of healthy participants. We recruited 812 healthy individuals (59.3 ± 14.0 years, 407 females, and 405 males) who underwent three-dimensional T1-weighted magnetic resonance imaging. Similarity-based gray matter networks were constructed, and the following network properties were calculated: normalized clustering, normalized path length, and small-world coefficients. The predicted brain age was computed using a support-vector regression model. We evaluated the network alterations related to age and sex. Additionally, we examined the correlations between the network properties and predicted brain age and compared them with the correlations between the network properties and chronological age. The brain network retained efficient small-world properties regardless of age; however, reduced small-world properties were observed with advancing age. Although women exhibited higher network properties than men and similar age-related network declines as men in the subjects aged < 70 years, faster age-related network declines were observed in women, leading to no differences in sex among the participants aged ≥ 70 years. Brain age correlated well with network properties compared to chronological age in participants aged ≥ 70 years. Although the brain network retained small-world properties, it moved towards randomized networks with aging. Faster age-related network disruptions in women were observed than in men among the elderly. Our findings provide new insights into network alterations underlying aging.

Correlation between the regional brain volume and glymphatic system activity in progressive supranuclear palsy.

INTRODUCTION: Tau protein accumulation in the brain is thought to be one of the causes of progressive supranuclear palsy (PSP). The glymphatic system was discovered a decade ago as a waste drainage system in the brain that promotes the elimination of amyloid-beta and tau protein. We here evaluated the relationships between glymphatic system activity and regional brain volumes in PSP patients. METHOD: Subjects were 24 patients with PSP and 42 healthy participants who underwent diffusion tensor imaging (DTI). We computed the diffusion tensor image analysis along the perivascular space (DTI­ALPS) index as a proxy of glymphatic system activity, and estimated the relationships between the DTI­ALPS index and regional brain volume in PSP patients by whole-brain and region-of-interest analyses, including analyses of the midbrain and third and lateral ventricles. RESULTS: The DTI­ALPS index was significantly lower in patients with PSP, compared with healthy subjects. Further, there were significant correlations between the DTI­ALPS index and the regional brain volumes in the midbrain tegmentum, pons, right frontal lobe, and lateral ventricles in patients with PSP. CONCLUSIONS: Our data suggest that the DTI­ALPS index is a good biomarker for PSP and might be effective to distinguish PSP from other neurocognitive disorders.

Clinical impact of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer's disease: a multicenter study.

OBJECTIVE: Amyloid positron emission tomography (PET) can reliably detect senile plaques and fluorinated ligands are approved for clinical use. However, the clinical impact of amyloid PET imaging is still under investigation. The aim of this study was to evaluate the diagnostic impact and clinical utility in patient management of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer's disease (AD). We also aimed to determine the cutoffs for amyloid positivity for quantitative measures by investigating the agreement between quantitative and visual assessments. METHODS: Ninety-nine patients suspected of having AD underwent 18F-florbetapir PET at five institutions. Site-specialized physicians provided a diagnosis of AD or non-AD with a percentage estimate of their confidence and their plan for patient management in terms of medication, prescription dosage, additional diagnostic tests, and care planning both before and after receiving the amyloid imaging results. A PET image for each patient was visually assessed and dichotomously rated as either amyloid-positive or amyloid-negative by four board-certified nuclear medicine physicians. The PET images were also quantitatively analyzed using the standardized uptake value ratio (SUVR) and Centiloid (CL) scale. RESULTS: Visual interpretation obtained 48 positive and 51 negative PET scans. The amyloid PET results changed the AD and non-AD diagnosis in 39 of 99 patients (39.3%). The change rates of 26 of the 54 patients (48.1%) with a pre-scan AD diagnosis were significantly higher than those of 13 of the 45 patients with a pre-scan non-AD diagnosis (χ2 = 5.334, p = 0.0209). Amyloid PET results also resulted in at least one change to the patient management plan in 42 patients (42%), mainly medication (20 patients, 20%) and care planning (25 patients, 25%). Receiver-operating characteristic analysis determined the best agreement of the quantitative assessments and visual interpretation of PET scans to have an area under the curve of 0.993 at an SUVR of 1.19 and CL of 25.9. CONCLUSION: Amyloid PET using 18F-florbetapir PET had a substantial clinical impact on AD and non-AD diagnosis and on patient management by enhancing diagnostic confidence. In addition, the quantitative measures may improve the visual interpretation of amyloid positivity.

Long-term treatment with ALK inhibitors for postoperative recurrence of ALK-rearranged lung cancer.

We encountered a 40-year-old female patient who developed, in chronological order, carcinomatous pleuritis and lymphangitis, multiple lymph node metastases, brain metastases, and intramedullary spinal cord metastases after resection of lung adenocarcinoma followed by adjuvant chemotherapy. Echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) fusion gene, variant 2 was identified in her cancer cells. By changing the ALK inhibitors from the 1st to 3rd generation each time when metastases were identified and incorporating local treatments in a timely fashion, such as metastasectomy or radiation therapy, she has survived for more than 11 years since the start of treatment, while maintaining a good Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0. To our knowledge, this is the first reported case in which ALK fusion variant 2 was identified and prolonged disease control was achieved with the continuous prescription of ALK tyrosine kinase inhibitors (TKIs) and timely consolidative treatments.

Harmonized Z-Scores Calculated from a Large-Scale Normal MRI Database to Evaluate Brain Atrophy in Neurodegenerative Disorders.

Alzheimer's disease (AD), the most common type of dementia in elderly individuals, slowly and progressively diminishes the cognitive function. Mild cognitive impairment (MCI) is also a significant risk factor for the onset of AD. Magnetic resonance imaging (MRI) is widely used for the detection and understanding of the natural progression of AD and other neurodegenerative disorders. For proper assessment of these diseases, a reliable database of images from cognitively healthy participants is important. However, differences in magnetic field strength or the sex and age of participants between a normal database and an evaluation data set can affect the accuracy of the detection and evaluation of neurodegenerative disorders. We developed a brain segmentation procedure, based on 30 Japanese brain atlases, and suggest a harmonized Z-score to correct the differences in field strength and sex and age from a large data set (1235 cognitively healthy participants), including 1.5 T and 3 T T1-weighted brain images. We evaluated our harmonized Z-score for AD discriminative power and classification accuracy between stable MCI and progressive MCI. Our procedure can perform brain segmentation in approximately 30 min. The harmonized Z-score of the hippocampus achieved high accuracy (AUC = 0.96) for AD detection and moderate accuracy (AUC = 0.70) to classify stable or progressive MCI. These results show that our method can detect AD with high accuracy and high generalization capability. Moreover, it may discriminate between stable and progressive MCI. Our study has some limitations: the age groups in the 1.5 T data set and 3 T data set are significantly different. In this study, we focused on AD, which is primarily a disease of elderly patients. For other diseases in different age groups, the harmonized Z-score needs to be recalculated using different data sets.

Free water derived by multi-shell diffusion MRI reflects tau/neuroinflammatory pathology in Alzheimer's disease.

Introduction: Free-water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods: Seventy-one participants underwent multi-shell diffusion MRI, 18F-THK5351 PET, 11C-Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) (n = 40) and AD-spectrum group (AD-S) (n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results: In AD-S group, there was a significant positive correlation between FW and 18F-THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18F-THK5351 and cognitive function in the same regions. Discussion: FW imaging could be a biomarker for tau in AD alongside clinical correlations.

Relationships Between the Deposition of Amyloid-ß and Tau Protein and Glymphatic System Activity in Alzheimer's Disease: Diffusion Tensor Image Study.

BACKGROUND: Amyloid-ß (Aß) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aß and tau protein. OBJECTIVE: We evaluated the relationships between the glymphatic system activity and the Aß and tau protein deposition. METHODS: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography (PET) using with the Aß tracer: 11C-PiB and the tau/inflammatory tracer: 18F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity, and estimated the relationships between the DTI-ALPS index and Aß and tau protein/inflammatory deposition. RESULTS: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. CONCLUSION: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aß and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity.

Upper cerebellar glucose hypermetabolism in patients with temporal lobe epilepsy and interictal psychosis.

OBJECTIVE: Psychosis is an important comorbidity in epilepsy, but its pathophysiology is still unknown. The imaging modality 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG PET) is widely used to measure brain glucose metabolism, and we speculated that 18 F-FDG PET may detect characteristic alteration patterns in individuals with temporal lobe epilepsy (TLE) and psychosis. METHODS: We enrolled 13 patients with TLE and interictal psychosis (TLE-P) and 21 patients with TLE without psychosis (TLE-N). All underwent interictal 18 F-FDG-PET scanning. Statistical Parametric Mapping (SPM)12 software was used for the normalization process, and we performed a voxel-wise comparison of the TLE-P and TLE-N groups. RESULTS: Cerebral hypometabolic areas were observed in the ipsilateral temporal pole to hippocampus in both patient groups. In the TLE-P group, the voxel-wise comparison revealed significantly increased 18 F-FDG signals in the upper cerebellum, superior cerebellar peduncle, and midbrain. There were no significant between-group metabolic differences around the focus or other cerebral areas. SIGNIFICANCE: Our results demonstrated significant hypermetabolism around the upper cerebellum in patients with TLE and interictal psychosis compared to patients with TLE without psychosis. These findings may reflect the involvement of the cerebellum in the underlying neurobiology of interictal psychosis and could contribute to a better understanding of this disorder.