Multi-Ethnic Norms for Volumes of Subcortical and Lobar Brain Structures Measured by Neuro I: Ethnicity May Improve the Diagnosis of Alzheimer's Disease1.

Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59-89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, ΔAUC = + 0.04, D = 4.10, p < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases.

Correlation between monosaccharide, oligosaccharide, and microbial community profile changes in traditional soybean brick (meju) fermentation.

Meju is essential for making diverse traditional fermented soybean foods in Korea. To understand the changes in carbohydrates during fermentation, we aimed to identify autochthonous microorganisms from spontaneously fermented meju and compare the alterations in monosaccharides and oligosaccharides throughout the fermentation process. Microbial diversity was determined using a metabarcoding approach, and monosaccharide and oligosaccharide profiles were obtained by HPLC-Q-TOF MS and HPLC-MS/MS analyses, respectively. The dominant bacterial genera were Weissella, Lactobacillus, and Leuconostoc, while Mucor was highly abundant in the fungal community. The total monosaccharide content increased from Day 0 to Day 50, with the highest amount being 4.37 mg/g. Oligosaccharide profiling revealed the degradation of soybean dietary fiber during fermentation, and novel oligosaccharide structures were also discovered. Correlation analysis revealed that the fungus Mucor was positively related to pentose-containing oligosaccharides, galactose, and galacturonic acid, indicating that Mucor may degrade soybean dietary fibers such as xylogalacturonan, arabinogalactan, and rhamnogalacturonan. The negative relationships between the abundances of Weissella and oligo- and monosaccharides suggested that the bacteria may utilize saccharides for fermentation. These findings provide insights into the mechanisms underlying carbohydrate degradation and utilization; the key components involved in saccharide transformation that contribute to the characteristics of traditional meju were subsequently identified.

Comparative anatomy of the dentate mossy cells in non-human primates: their spatial distributions and axonal projections compared with mouse mossy cells.

Glutamatergic mossy cells (MCs) mediate associational and commissural connectivity, exhibiting significant heterogeneity along the septotemporal axis of the mouse dentate gyrus (DG). However, it remains unclear whether the neuronal features of MCs are conserved across mammals. This study compares the neuroanatomy of MCs in the DG of mice and monkeys. The MC marker, calretinin, distinguishes two subpopulations: septal and temporal. Dual-colored fluorescence labeling is utilized to compare the axonal projection patterns of these subpopulations. In both mice and monkeys, septal and temporal MCs project axons across the longitudinal axis of the ipsilateral DG, indicating conserved associational projections. However, unlike in mice, no MC subpopulations in monkeys make commissural projections to the contralateral DG. In monkeys, temporal MCs send associational fibers exclusively to the inner molecular layer, while septal MCs give rise to wide axonal projections spanning multiple molecular layers, akin to equivalent MC subpopulations in mice. Despite conserved septotemporal heterogeneity, interspecies differences are observed in the topological organization of septal MCs, particularly in the relative axonal density in each molecular layer along the septotemporal axis of the DG. In summary, this comparative analysis sheds light on both conserved and divergent features of MCs in the DG of mice and monkeys. These findings have implications for understanding functional differentiation along the septotemporal axis of the DG and contribute to our knowledge of the anatomical evolution of the DG circuit in mammals.Significance Statement This study investigates glutamatergic mossy cells (MCs) in the dentate gyrus (DG) of mice and monkeys, revealing both conserved and species-specific features. While associational projections are consistent across species, monkeys lack the commissural projections of MCs seen in mice. Additionally, the topological organization of septal MC axons differs, particularly in relative axonal density along the septotemporal axis. These findings provide insights into the anatomical evolution of the DG circuit in mammals, shedding light on potential functional distinctions. The study enhances our understanding of neural circuitry, offering a platform for further exploration into the intricate relationship between structure and function in the mammalian brain.

Advanced Immunolabeling Method for Optical Volumetric Imaging Reveals Dystrophic Neurites of Dopaminergic Neurons in Alzheimer's Disease Mouse Brain.

Optical brain clearing combined with immunolabeling is valuable for analyzing molecular tissue structures, including complex synaptic connectivity. However, the presence of aberrant lipid deposition due to aging and brain disorders poses a challenge for achieving antibody penetration throughout the entire brain volume. Herein, we present an efficient brain-wide immunolabeling method, the immuno-active clearing technique (iACT). The treatment of brain tissues with a zwitterionic detergent, specifically SB3-12, significantly enhanced tissue permeability by effectively mitigating lipid barriers. Notably, Quadrol treatment further refines the methodology by effectively eliminating residual detergents from cleared brain tissues, subsequently amplifying volumetric fluorescence signals. Employing iACT, we uncover disrupted axonal projections within the mesolimbic dopaminergic (DA) circuits in 5xFAD mice. Subsequent characterization of DA neural circuits in 5xFAD mice revealed proximal axonal swelling and misrouting of distal axonal compartments in proximity to amyloid-beta plaques. Importantly, these structural anomalies in DA axons correlate with a marked reduction in DA release within the nucleus accumbens. Collectively, our findings highlight the efficacy of optical volumetric imaging with iACT in resolving intricate structural alterations in deep brain neural circuits. Furthermore, we unveil the compromised integrity of DA pathways, contributing to the underlying neuropathology of Alzheimer's disease. The iACT technique thus holds significant promise as a valuable asset for advancing our understanding of complex neurodegenerative disorders and may pave the way for targeted therapeutic interventions. The axonal projection of DA neurons in the septum and the NAc showed dystrophic phenotypes such as growth cone-like enlargement of the axonal terminus and aggregated neurites. Brain-wide imaging of structural defects in the neural circuits was facilitated with brain clearing and antibody penetration assisted with SB3-12 and Quadrol pre-treatment. The whole volumetric imaging process could be completed in a week with the robust iACT method. Created with https://www.biorender.com/ .

EBP50 is a key molecule for the Schwann cell-axon interaction in peripheral nerves.

Peripheral nerve injury disrupts the Schwann cell-axon interaction and the cellular communication between them. The peripheral nervous system has immense potential for regeneration extensively due to the innate plastic potential of Schwann cells (SCs) that allows SCs to interact with the injured axons and exert specific repair functions essential for peripheral nerve regeneration. In this study, we show that EBP50 is essential for the repair function of SCs and regeneration following nerve injury. The increased expression of EBP50 in the injured sciatic nerve of control mice suggested a significant role in regeneration. The ablation of EBP50 in mice resulted in delayed nerve repair, recovery of behavioral function, and remyelination following nerve injury. EBP50 deficiency led to deficits in SC functions, including proliferation, migration, cytoskeleton dynamics, and axon interactions. The adeno-associated virus (AAV)-mediated local expression of EBP50 improved SCs migration, functional recovery, and remyelination. ErbB2-related proteins were not differentially expressed in EBP50-deficient sciatic nerves following injury. EBP50 binds and stabilizes ErbB2 and activates the repair functions to promote regeneration. Thus, we identified EBP50 as a potent SC protein that can enhance the regeneration and functional recovery driven by NRG1-ErbB2 signaling, as well as a novel regeneration modulator capable of potential therapeutic effects.

Primary cilia-mediated regulation of microglial secretion in Alzheimer's disease.

Alzheimer's disease (AD) is a brain disorder manifested by a gradual decline in cognitive function due to the accumulation of extracellular amyloid plaques, disruptions in neuronal substance transport, and the degeneration of neurons. In affected neurons, incomplete clearance of toxic proteins by neighboring microglia leads to irreversible brain inflammation, for which cellular signaling is poorly understood. Through single-cell transcriptomic analysis, we discovered distinct regional differences in the ability of microglia to clear damaged neurites. Specifically, microglia in the septal region of wild type mice exhibited a transcriptomic signature resembling disease-associated microglia (DAM). These lateral septum (LS)-enriched microglia were associated with dense axonal bundles originating from the hippocampus. Further transcriptomic and proteomic approaches revealed that primary cilia, small hair-like structures found on cells, played a role in the regulation of microglial secretory function. Notably, primary cilia were transiently observed in microglia, and their presence was significantly reduced in microglia from AD mice. We observed significant changes in the secretion and proteomic profiles of the secretome after inhibiting the primary cilia gene intraflagellar transport particle 88 (Ift88) in microglia. Intriguingly, inhibiting primary cilia in the septal microglia of AD mice resulted in the expansion of extracellular amyloid plaques and damage to adjacent neurites. These results indicate that DAM-like microglia are present in the LS, a critical target region for hippocampal nerve bundles, and that the primary ciliary signaling system regulates microglial secretion, affecting extracellular proteostasis. Age-related primary ciliopathy probably contributes to the selective sensitivity of microglia, thereby exacerbating AD. Targeting the primary ciliary signaling system could therefore be a viable strategy for modulating neuroimmune responses in AD treatments.

Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease.

Dystrophic neurites (DNs) are abnormal axons and dendrites that are swollen or deformed in various neuropathological conditions. In Alzheimer's disease (AD), DNs play a crucial role in impairing neuronal communication and function, and they may also contribute to the accumulation and spread of amyloid beta (Aß) in the brain of AD patients. However, it is still a challenge to understand the DNs of specific neurons that are vulnerable to Aß in the pathogenesis of AD. To shed light on the development of radiating DNs, we examined enriched dystrophic hippocampal axons in a mouse model of AD using a three-dimensional rendering of projecting neurons. We employed the anterograde spread of adeno-associated virus (AAV)1 and conducted proteomic analysis of synaptic compartments obtained from hippocampo-septal regions. Our findings revealed that DNs were formed due to synaptic loss at the axon terminals caused by the accumulation of extracellular vesicle (EV). Abnormal EV-mediated transport and exocytosis were identified in association with primary cilia, indicating their involvement in the accumulation of EVs at presynaptic terminals. To further address the regulation of DNs by primary cilia, we conducted knockdown of the Ift88 gene in hippocampal neurons, which impaired EV-mediated secretion of Aß and promoted accumulation of axonal spheroids. Using single-cell RNA sequencing, we identified the septal projecting hippocampal somatostatin neurons (SOM) as selectively vulnerable to Aß with primary cilia dysfunction and vesicle accumulation. Our study suggests that DNs in AD are initiated by the ectopic accumulation of EVs at the neuronal axon terminals, which is affected by neuronal primary cilia.

Impact of the circadian nuclear receptor REV-ERBα in dorsal raphe 5-HT neurons on social interaction behavior, especially social preference.

Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERBα, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erbα in dorsal raphe (DR) 5-HT neurons (5-HTDR-specific REV-ERBα cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erbα in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erbα in 5-HTDR-specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HTDR-specific REV-ERBα cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERBα in regulating social interaction behaviors.

Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

Clinical determinants of apathy and its impact on health-related quality of life in early Parkinson disease.

Apathy is a common non-motor symptom of Parkinson disease (PD) that can affect the health-related quality of life (HRQoL) of patients and caregivers. This study aimed to investigate the clinical determinants of apathy and its impact on HRQoL in patients with early PD. We enrolled 324 patients with early PD with modified Hoehn-Yahr stages 1 to 3 and a disease duration ≤5 years. Demographic information was obtained, and motor and non-motor symptoms were evaluated with relevant scales. Apathy was present in 110 of 324 (33.9%) patients. Compared with patients with non-apathetic PD, those with apathetic PD had significantly higher modified Hoehn-Yahr stage, Unified Parkinson's Disease Rating Scale-II (UPDRS-II) score, Non-Motor Symptoms Scale (NMSS) total score, Beck Depression Inventory (BDI) score, and Parkinson's Disease Questionnaire-8 (PDQ-8) score. Clinical variables independently associated with the Apathy Evaluation Scale (AES) score were NMSS domain 3 score and BDI score. The univariate regression analysis revealed that the PDQ-8 score was significantly associated with age; disease duration; formal education duration; and UPDRS-III, UPDRS-II, NMSS total, Mini-Mental Status Examination, BDI, Beck Anxiety Inventory, and AES scores. Independent predictors of the PDQ-8 score in the multivariate regression analysis were UPDRS-III, UPDRS-II, NMSS total, NMSS domain 3, Beck Anxiety Inventory, and AES scores. In the present study, apathy was an independent predictor of HRQoL in patients with early PD. Therefore, identifying and managing apathy could help improve HRQoL in patients with early PD.

Brain heterotopia formation by ciliopathic breakdown of neuroepithelial and blood-cerebrospinal fluid barriers.

The developmental functions of primary cilia and the downstream signaling pathways have been widely studied; however, the roles of primary cilia in the developing neurovascular system are not clearly understood. In this study, we found that ablation of genes encoding ciliary transport proteins such as intraflagellar transport homolog 88 (Ift88) and kinesin family member 3a (Kif3a) in cortical radial progenitors led to periventricular heterotopia during late mouse embryogenesis. Conditional mutation of primary cilia unexpectedly caused breakdown of both the neuroepithelial lining and the blood-choroid plexus barrier. Choroidal leakage was partially caused by enlargement of the choroid plexus in the cilia mutants. We found that the choroid plexus expressed platelet-derived growth factor A (Pdgf-A) and that Pdgf-A expression was ectopically increased in cilia-mutant embryos. Cortices obtained from embryos in utero electroporated with Pdgfa mimicked periventricular heterotopic nodules of the cilia mutant. These results suggest that defective ciliogenesis in both cortical progenitors and the choroid plexus leads to breakdown of cortical and choroidal barriers causing forebrain neuronal dysplasia, which may be related to developmental cortical malformation.

Knee osteoarthritis accelerates amyloid beta deposition and neurodegeneration in a mouse model of Alzheimer's disease.

Knee osteoarthritis (OA) is characterized by knee cartilage degeneration and secondary bone hyperplasia, resulting in pain, stiffness, and gait disturbance. The relationship between knee OA and neurodegenerative diseases is still unclear. This study used an Alzheimer's disease (AD) mouse model to observe whether osteoarthritis accelerates dementia progression by analyzing brain histology and neuroinflammation. Knee OA was induced by destabilizing the medial meniscus (DMM) in control (WT) and AD (5xFAD) mice before pathological symptoms. Mouse knee joints were scanned with a micro-CT scanner. A sham operation was used as control. Motor and cognitive abilities were tested after OA induction. Neurodegeneration, ß-amyloid plaque formation, and neuroinflammation were analyzed by immunostaining, Western blotting, and RT-PCR in brain tissues. Compared with sham controls, OA in AD mice increased inflammatory cytokine levels in brain tissues. Furthermore, OA significantly increased ß-amyloid deposition and neuronal loss in AD mice compared to sham controls. In conclusion, knee OA accelerated amyloid plaque deposition and neurodegeneration in AD-OA mice, suggesting that OA is a risk factor for AD.

LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient's reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.

Can hippocampal subfield measures supply information that could be used to improve the diagnosis of Alzheimer's disease?

The diagnosis of Alzheimer's disease (AD) needs to be improved. We investigated if hippocampal subfield volume measured by structural imaging, could supply information, so that the diagnosis of AD could be improved. In this study, subjects were classified based on clinical, neuropsychological, and amyloid positivity or negativity using PET scans. Data from 478 elderly Korean subjects grouped as cognitively unimpaired ß-amyloid-negative (NC), cognitively unimpaired ß-amyloid-positive (aAD), mild cognitively impaired ß-amyloid-positive (pAD), mild cognitively impaired-specific variations not due to dementia ß-amyloid-negative (CIND), severe cognitive impairment ß-amyloid-positive (ADD+) and severe cognitive impairment ß-amyloid-negative (ADD-) were used. NC and aAD groups did not show significant volume differences in any subfields. The CIND did not show significant volume differences when compared with either the NC or the aAD (except L-HATA). However, pAD showed significant volume differences in Sub, PrS, ML, Tail, GCMLDG, CA1, CA4, HATA, and CA3 when compared with the NC and aAD. The pAD group also showed significant differences in the hippocampal tail, CA1, CA4, molecular layer, granule cells/molecular layer/dentate gyrus, and CA3 when compared with the CIND group. The ADD- group had significantly larger volumes than the ADD+ group in the bilateral tail, SUB, PrS, and left ML. The results suggest that early amyloid depositions in cognitive normal stages are not accompanied by significant bilateral subfield volume atrophy. There might be intense and accelerated subfield volume atrophy in the later stages associated with the cognitive impairment in the pAD stage, which subsequently could drive the progression to AD dementia. Early subfield volume atrophy associated with the ß-amyloid burden may be characterized by more symmetrical atrophy in CA regions than in other subfields. We conclude that the hippocampal subfield volumetric differences from structural imaging show promise for improving the diagnosis of Alzheimer's disease.

Changes in Cytochrome C Oxidase Redox State and Hemoglobin Concentration in Rat Brain During 810 nm Irradiation Measured by Broadband Near-Infrared Spectroscopy.

Objective: The effects of 810 nm light-emitting diode (LED) photobiomodulation (PBM) on cerebral metabolism and cerebral hemodynamic were investigated by using a broadband near-infrared spectroscopy (bb-NIRS) under anesthesia conditions with isoflurane. Background data: PBM was supposed to increase cerebral hemodynamic and cerebral metabolism. There has been no study about the effect of 810 nm LED stimulation on cerebral hemodynamic and cerebral metabolism in vivo by using bb-NIRS measurement. Methods: PBM was applied to seven Sprague-Dawley rats at 50 mW/cm2 power density. The changes in hemoglobin concentration (ΔHbO2 and ΔHHb) and oxidized cytochrome c oxidase (CCO) concentration (ΔoxCCO) were measured using a bb-NIRS. The total hemoglobin and the difference in hemoglobin concentration changes were calculated by summation and difference of ΔHbO2 and ΔHHb, respectively. Results: PBM evoked the gradual increases of ΔHbO2 (+7.7 µM vs. baseline, p = 0.008), ΔHbT (+9.5 µM vs. baseline, p = 0.0044), and ΔHbD (+5.9 µM vs. baseline, p > 0.05) during light stimulation. Meanwhile, ΔoxCCO (-3.5 µM vs. baseline, p = 0.0019) was significantly decreased right after the onset of stimulation. Conclusions: PBM with 810 nm LED (50 mW/cm2) increased cerebral oxygenation and blood volume as expected. However, oxidized CCO concentration was decreased, which was contrary to most previous studies. The two pathways of PBM effects on mitochondria and the inhibition of complex I by isoflurane were suggested to explain the decreased ΔoxCCO during PBM, but further study is required for the verification.

Pharmacological Rescue with SR8278, a Circadian Nuclear Receptor REV-ERBα Antagonist as a Therapy for Mood Disorders in Parkinson's Disease.

Parkinson's disease is a neurodegenerative disease characterized by progressive dopaminergic neuronal loss. Motor deficits experienced by patients with Parkinson's disease are well documented, but non-motor symptoms, including mood disorders associated with circadian disturbances, are also frequent features. One common phenomenon is "sundowning syndrome," which is characterized by the occurrence of neuropsychiatric symptoms at a specific time (dusk), causing severe quality of life challenges. This study aimed to elucidate the underlying mechanisms of sundowning syndrome in Parkinson's disease and their molecular links with the circadian clock. We demonstrated that 6-hydroxydopamine (6-OHDA)-lesioned mice, as Parkinson's disease mouse model, exhibit increased depression- and anxiety-like behaviors only at dawn (the equivalent of dusk in human). Administration of REV-ERBα antagonist, SR8278, exerted antidepressant and anxiolytic effects in a circadian time-dependent manner in 6-OHDA-lesioned mice and restored the circadian rhythm of mood-related behaviors. 6-OHDA-lesion altered DAergic-specific Rev-erbα and Nurr1 transcription, and atypical binding activities of REV-ERBα and NURR1, which are upstream nuclear receptors for the discrete tyrosine hydroxylase promoter region. SR8278 treatment restored the binding activities of REV-ERBα and NURR1 to the tyrosine hydroxylase promoter and the induction of enrichment of the R/N motif, recognized by REV-ERBα and NURR1, as revealed by ATAC-sequencing; therefore, tyrosine hydroxylase expression was elevated in the ventral tegmental area of 6-OHDA-injected mice, especially at dawn. These results indicate that REV-ERBα is a potential therapeutic target, and its antagonist, SR8278, is a potential drug for mood disorders related to circadian disturbances, namely sundowning syndrome, in Parkinson's disease.

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aß plaques and brain rhythms in 5×FAD mice.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by amyloid-ß (Aß) plaques and tauopathy. Reducing Aß has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. METHODS: We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aß levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. RESULTS: We found that the total Aß42 levels, especially insoluble Aß42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aß plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. CONCLUSION: These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aß load and improving brain connectivity.

Multi-Racial Normative Data for Lobar and Subcortical Brain Volumes in Old Age: Korean and Caucasian Norms May Be Incompatible With Each Other†.

Brain aging is becoming an increasingly important topic, and the norms of brain structures are essential for diagnosing neurodegenerative diseases. However, previous studies of the aging brain have mostly focused on Caucasians, not East Asians. The aim of this paper was to examine ethnic differences in the aging process of brain structures or to determine to what extent ethnicity affects the normative values of lobar and subcortical volumes in clinically normal elderly and the diagnosis in multi-racial patients with Alzheimer's disease (AD). Lobar and subcortical volumes were measured using FreeSurfer from MRI data of 1,686 normal Koreans (age range 59-89) and 851 Caucasian, non-Hispanic subjects in the ADNI and OASIS datasets. The regression models were designed to predict brain volumes, including ethnicity, age, sex, intracranial volume (ICV), magnetic field strength (MFS), and MRI scanner manufacturers as independent variables. Ethnicity had a significant effect for all lobar (|ß| > 0.20, p < 0.001) and subcortical regions (|ß| > 0.08, p < 0.001) except left pallidus and bilateral ventricles. To demonstrate the validity of the z-score for AD diagnosis, 420 patients and 420 normal controls were selected evenly from the Korean and Caucasian datasets. The four validation groups divided by race and diagnosis were matched on age and sex using a propensity score matching. We analyzed whether and to what extent the ethnicity adjustment improved the diagnostic power of the logistic regression model that was built using the only z-scores of six regions: bilateral temporal cortices, hippocampi, and amygdalae. The performance of the classifier after ethnicity adjustment was significantly improved compared with the classifier before ethnicity adjustment (ΔAUC = 0.10, D = 7.80, p < 0.001; AUC comparison test using bootstrap). Korean AD dementia patients may not be classified by Caucasian norms of brain volumes because the brain regions vulnerable to AD dementia are bigger in normal Korean elderly peoples. Therefore, ethnicity is an essential factor in establishing normative data for regional volumes in brain aging and applying it to the diagnosis of neurodegenerative diseases.