DOI： 10.1101/2025.07.31.668024

PubMed

DOI： 10.1177/13872877251351220

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

The ventral striatum (VS) is a key brain region for reward processing and motivation, and its dysfunctions have been implicated in psychiatric disorders such as apathy and obsessive-compulsive disorder. Although functional heterogeneity within the VS has been well established in rodents, its relevance and mechanisms in primates remain unclear. To address this issue, we performed bilateral pharmacological inactivation of the VS in two male macaque monkeys using muscimol, a GABAA receptor agonist. Precise targeting was achieved through computed tomography and magnetic resonance imaging. Behavioral effects were evaluated using two methods: a goal-directed task with variable rewards and analysis of spontaneous behavior. Our results demonstrated that anterior (a)VS inactivation induced a hypoactivity state that we termed "resting," whereas posterior (p)VS inactivation elicited compulsive-like "checking" behaviors. Notably, neither the aVS nor the pVS inactivation affected reward value or drive processing, thus differentiating aVS and pVS from those involved in incentive motivation, such as the rostromedial caudate and ventral pallidum. Retrograde tracing demonstrated distinct anatomical projection patterns for the aVS and pVS, supporting their functional segregation. Together, the present results suggest the functional heterogeneity of the primate VS along its anterior-posterior axis, with the aVS and pVS participating in distinct motivational control circuits. Our findings may have important implications for understanding the neural mechanisms of psychiatric disorders and for the development of new therapeutic approaches.Significance Statement The ventral striatum (VS) is a core brain region that is involved in motivation and reward-based behaviors. Its dysfunction is implicated in psychiatric disorders such as apathy and obsessive-compulsive disorder. In macaque monkeys, we used imaging-guided pharmacological manipulations to reveal that the anterior and posterior VS subregions have distinct roles in motivation, independent of the incentive or reward drive. Specifically, anterior VS inactivation induced a hypoactive state, whereas posterior VS inactivation elicited compulsive-like behaviors. These findings reveal distinct motivational mechanisms within the primate VS, thus offering valuable insights into the neural basis of psychiatric disorders and identifying promising therapeutic targets.

DOI： 10.1523/JNEUROSCI.2430-24.2025

PubMed

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. Virus titer and the presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.

DOI： 10.7554/elife.105815.1

Ro5-4864(輸送体蛋白質(TSPO)リガンド)のT細胞応答への影響を、2,4-ジニトロ-1-フルオロベンゼン(DNFB)誘発性接触過敏症モデルを用いて検討した。感作期にRo5-4864を投与すると、リンパ節のCD4+およびCD8+ T細胞の数と活性が低下し、皮膚炎症が軽減された。Ro5-4864処理マウス由来T細胞の養子移植でも接触過敏症反応が抑制された。Ro5-4864はT細胞活性化時の増殖、ATPおよび乳酸産生を抑制し、これらの効果はTSPO欠損細胞でも維持された。以上より、Ro5-4864はTSPO非依存的にT細胞の一次応答を抑制し、接触過敏反応を制御する可能性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.

DOI： 10.1016/j.ejcb.2025.151484

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

18F-SPAL-T-06 and 18F-C05-05 are two novel positron emission tomography (PET) radioligands targeting α-synuclein fibrils. Our study aimed to evaluate the biodistribution, safety, and radiation dosimetry of each tracer in humans. Biodistribution and radiation dosimetry studies were carried out with two healthy volunteers for each tracer, 18F-SPAL-T-06 (one female and one male volunteer, both aged 63 years) and 18F-C05-05 (one female and one male volunteer, aged 63 and 73 years, respectively). After injection of either tracer, dynamic PET images were acquired from head to upper thigh. Effective dose of each tracer was estimated using OLINDA/EXM Version 2.2. Injection of either of the tracers caused no adverse effects. Greatest uptake of both tracers was observed in the liver and small intestine. The estimated absorbed doses were highest in the biliary tract, followed by the lower large intestinal wall. Effective doses were 35.9 µSv/MBq for 18F-SPAL-T-06 and 30.5 µSv/MBq for 18F-C05-05. 18F-SPAL-T-06 and 18F-C05-05 are safe for in vivo PET imaging of humans. Their mean effective doses were 6.6 mSv for 18F-SPAL-T-06 and 5.6 mSv for 18F-C05-05 when 185 MBq of either tracer was given to a subject, and they were comparable to other amyloid and tau PET tracers labelled with 18F.Trial registration Trial registration number: jRCTs031210180, Registered date: 2nd July 2021 (18F-SPAL-T-06) https://jrct.niph.go.jp/en-latest-detail/jRCTs031210180 and Trial registration number: jRCTs031220123, Registered date: 9th June 2022 (18F-C05-05) https://jrct.niph.go.jp/en-latest-detail/jRCTs031220123 .

DOI： 10.1038/s41598-025-93520-5

PubMed

症例は68歳女性で、67歳時に言葉が出にくくなり、書字も困難な状況が頻繁に現れていた。周囲の人は、患者に視覚性失認の症状があることに気づいていた。神経変性疾患の病歴・家族歴はなかった。当初はアルツハイマー病の一型としてのposterior cortical atrophyと疑われ、ドネペジル治療が1年間行われたが、失語症が進行したため当院へ紹介された。神経学的診察の結果、logopenic型の原発性進行性失語症と臨床診断した。紹介受診から1年後には寡動と右側の筋硬直を発症した。L-ドーパで11ヵ月間治療したが効果は示されず、大脳皮質基底核症候群と診断した。それから3年後には無動性緘黙に陥り、さらに2年後に誤嚥性肺炎のため死亡した。剖検が行われ、その神経病理学的解析では脳皮質にび漫性の萎縮、重度の神経細胞喪失、線維性グリオーシスが観察された。神経細胞では、細胞質内・核内の封入体などにリン酸化TDP-43の免疫反応が認められた。ウェスタンブロット法ではリン酸化TDP-43の全長蛋白質(45kDa)と断片蛋白質(23kDa)の存在が示された。A型前頭側頭葉変性症(FTLD)のFTLD-TDP亜型と病理診断した。全エクソーム配列解析ではGRN遺伝子に病原性変異(c.87dupC)が発見された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND AND OBJECTIVES: A previous postmortem study of men with Christianson syndrome, a disorder caused by loss-of-function mutations in the gene SLC9A6, reported a mechanistic link between pathologic tau accumulation and progressive symptoms such as cerebellar atrophy and cognitive decline. This study aimed to characterize the relationships between neuropathologic manifestations and tau accumulation in heterozygous women with SLC9A6 mutation. METHODS: We conducted a multimodal neuroimaging and plasma biomarker study on 3 middle-aged heterozygous women with SLC9A6 mutations (proband 1: mid-50s; proband 2: early 50s; proband 3: mid-40s) presenting with progressive extrapyramidal symptoms. Examinations included 11C-PiB PET; 18F-florzolotau PET; structural MRI; and plasma measures of neurofilament light chain (NfL) polypeptide, glial fibrillary acidic protein, phosphorylated (p)Tau181, Aβ40, and Aβ42. Neuroimaging results of all 3 patients were compared with those of 12 healthy age-matched women (49.8 ± 4.7 years) while plasma biomarker levels of probands 1 and 2 were compared with those of 14 age-matched healthy women (54.1 ± 9.0 years). RESULTS: Proband 1 was diagnosed with Parkinson disease while probands 2 and 3 were diagnosed with atypical parkinsonism. 11C-PiB PET results were negative in all patients. 18F-florzolotau PET revealed focal tau accumulations in all 3 patients, predominantly in the striatum contralateral to motor symptoms. Moreover, greater extrapyramidal symptom severity was associated with higher standardized uptake value ratios (SUVRs) for 18F-florzolotau in the striatum. Multiple comparisons showed significantly higher 18F-florzolotau SUVR values in both the caudate and putamen of proband 1, who exhibited the most severe extrapyramidal signs, while no significant increases in 18F-florzolotau SUVR values were detected in any brain region of probands 2 and 3. Structural MRI revealed slightly lower regional subcortical and gray matter volumes in all patients but not significant after multiple comparisons. Finally, plasma NfL concentration was significantly higher in probands 1 and 2 compared with healthy controls. DISCUSSION: Our 18F-florzolotau PET analysis revealed greater tau accumulation in the striatum of heterozygous women with SLC9A6 mutation associated with worsening extrapyramidal symptom severity. The heterozygosity of loss-of-function SLC9A6 mutations further suggests that tauopathy may be a primary contributor to extrapyramidal signs.

DOI： 10.1212/NXG.0000000000200235

PubMed

Abstract

We recently reported development of humanMAPTknock-in mice that carry single or double pathogenic mutations of frontotemporal dementia. However, it takes more than 14 months for the line with the most aggressive phenotypes to exhibit tau pathology without forming high-order tau oligomers, along with concomitant abnormal behavior. We thus generatedMAPTknock-in mice carrying triple mutations, among which theMAPT^{P301S;Int10+3;S320F}line exhibited robust pathology starting earlier than 6 months. Tau accumulation took place mainly in the thalamus, hypothalamus, amygdala and entorhinal cortex, but less so in the hippocampus, leading to synaptic loss, atrophy and behavioral abnormalities. CrossbreedingMAPT^{P301S;Int10+3;S320F}withAppknock-in miceApp^NL-G-Fresulted in the manifestation of tau pathology in the hippocampus and cortex. These mutant mice will be valuable tools for understanding the mechanisms of frontotemporal dementia, Alzheimer’s disease and other tauopathies.

DOI： 10.1101/2024.11.15.623736

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41398-024-03107-3

Publishing type：Research paper (scientific journal)  

The amyloid β peptide (Aβ), starting with pyroglutamate (pE) at position 3 and ending at position 42 (Aβ3pE-42), predominantly accumulates in the brains of Alzheimer’s disease. Consistently, donanemab, a therapeutic antibody raised against Aβ3pE-42, has been shown to be effective in recent clinical trials. Although the primary Aβ produced physiologically is Aβ1-40/42, an explanation for how and why this physiological Aβ is converted to the pathological form remains elusive. Here, we present experimental evidence that accounts for the aging-associated Aβ3pE-42 deposition: Aβ3pE-42 was metabolically more stable than other Aβx-42 variants; deficiency of neprilysin, the major Aβ-degrading enzyme, induced a relatively selective deposition of Aβ3pE-42 in both APP transgenic andAppknock-in mouse brains; Aβ3pE-42 deposition always colocalized with Pittsburgh compound B–positive cored plaques in APP transgenic mouse brains; and under aberrant conditions, such as a significant reduction in neprilysin activity, aminopeptidases, dipeptidyl peptidases, and glutaminyl-peptide cyclotransferase-like were up-regulated in the progression of aging, and a proportion of Aβ1-42 may be processed to Aβ3pE-42. Our findings suggest that anti-Aβ therapies are more effective if given before Aβ3pE-42 deposition.

DOI： 10.26508/lsa.202402650

International / domestic magazine：International journal  

DOI： 10.1186/s40035-024-00439-4

PubMed

Publishing type：Research paper (scientific journal)  

Abstract

Creating a mouse model that recapitulates human tau pathology is essential for developing strategies to intervene in tau-induced neurodegeneration. However, mimicking the pathological features seen in human pathology often involves a trade-off with artificial effects such as unexpected gene insertion and neurotoxicity from the expression system. To overcome these issues, we developed the rTKhomo mouse model by combining a transgenic CaMKII-tTA system with a P301L mutated 1N4R human tau knock-in at the Rosa26 locus with a C57BL/6J background. This model closely mimics human tau pathology, particularly in the hippocampal CA1 region, showing age-dependent tau accumulation, neuronal loss and neuroinflammation. Notably, whole-brain 3D staining and light-sheet microscopy revealed a spatial gradient of tau deposition from the entorhinal cortex to the hippocampus, similar to the spatial distribution of Braak neurofibrillary tangle staging. Furthermore, [18F]PM-PBB3 positron emission tomography imaging enabled the quantification and live monitoring of tau deposition. The rTKhomo mouse model shows potential as a promising next-generation preclinical tool for exploring the mechanisms of tauopathy and for developing interventions targeting the spatial progression of tau pathology.

DOI： 10.1093/braincomms/fcae326

PubMed

Other URL： https://academic.oup.com/braincomms/article-pdf/6/5/fcae326/59468071/fcae326.pdf

＜文献概要＞タウPETは,タウ凝集体に対して選択的に結合するトレーサーを用いて脳内タウ沈着を可視化する病態イメージング法である。2010年代初期に最初のタウPET薬が撮像されて以降,さまざまな改良が重ねられている。タウPETはアルツハイマー病およびその他のタウオパチーの診断や予後予測に有用である。しかし,タウPET薬の結合プロファイルは疾患によって大きく異なるため,タウPET所見の解釈に際しては疾患ごとの特性を理解しておく必要がある。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Tau positron emission tomography (PET) is a neuroimaging technique that visualizes tau deposition using PET tracers that selectively bind to tau aggregates. Studies have reported the diagnostic and prognostic value of tau PET in Alzheimer's disease and other tauopathies. However, the binding profiles of tau PET drugs vary widely across tauopathies; therefore, an accurate understanding of the disease-specific characteristics is essential for interpretation of tau PET findings. In this review, we discuss the properties of tau-PET agents and their applications in various diseases.

DOI： 10.11477/mf.1416202729

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT4 receptor (5-HT4R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT4R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT4R in the dCDh. We then examined the effects of a specific 5-HT4R antagonist infused into the dCDh. Blockade of 5-HT4R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT4R blockade because saline controls showed no such effect. The results demonstrate that 5-HT4Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT4R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.

DOI： 10.1038/s41598-024-70414-6

PubMed

85歳男性.1年前から仮名の読字困難を自覚.神経心理検査では仮名に選択的な失読,漢字優位の失書,構成障害を認めた.頭部MRIでは左後頭皮質に強い脳萎縮を認め,後部皮質萎縮症(posterior cortical atrophy,以下PCAと略記)と臨床診断した.髄液中アミロイドβ1-42は低下し,アミロイドPETでは後部帯状回・楔前部や前頭葉にプローブ集積を認めた一方,タウPETでは萎縮部位を含めてプローブ集積を認めなかった.レム睡眠行動障害およびmeta-iodobenzylguanidine(MIBG)心筋シンチグラフィにおける取り込み低下を認め,病因としてレビー小体病理の関与が示唆された.萎縮の左右差が強いPCAは稀であり,また神経変性疾患において仮名選択性の失読および漢字優位の失書を呈した報告は初めてである.(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates.

DOI： 10.1038/s41467-024-49570-w

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.

DOI： 10.1016/j.neuron.2024.05.006

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024.

DOI： 10.1002/ana.26962

PubMed

Publishing type：Research paper (scientific journal)  

A 68‐year‐old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L‐dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid β or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP‐43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP‐43 at 45 and 23 kDa, respectively, confirming the pathological diagnosis of type A FTLD‐TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD‐TDP should be included in the differential diagnosis of CBS.

DOI： 10.1111/neup.12980

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

DOI： 10.1002/mdc3.14042

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV-adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK-SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann-Whitney U test, p < 0.05) underwent partial correlation analysis, adjusting for age and sex, to assess its connection with neuropsychological test results. Compared with the control group, the rmTBI group showed significantly lower the MBs volume/TBV ratio (0.13 ± 0.05 vs. 0.19 ± 0.03 × 10-3, p < 0.001). The MBs volume/TBV ratio correlated with visual memory, as assessed, respectively, by the Rey-Osterrieth Complex Figure test delayed recall (ρ = 0.62, p < 0.001). In conclusion, retired athletes with rmTBI have MB atrophy, potentially contributing to memory impairment linked to the Papez circuit disconnection.

DOI： 10.1038/s41598-024-57383-6

PubMed

Ultrasound neuromodulation has become an innovative technology that enables non-invasive intervention in mammalian brain circuits with high spatiotemporal precision. Despite the expanding utility of ultrasound neuromodulation in the neuroscience research field and clinical applications, the molecular and cellular mechanisms by which ultrasound impacts neural activity in the brain are still largely unknown. Here, we report that transient receptor potential canonical 6 (TRPC6), a mechanosensitive non-selective cation channel, is essential for ultrasound neuromodulation of mammalian neurons in vitro and in vivo. We first demonstrated that ultrasound irradiation elicited rapid and robust Ca²⁺transients mediated via extracellular Ca²⁺influx in cultured mouse cortical and hippocampal neurons. Ultrasound-induced neuronal responses were massively diminished by blocking either the generation of action potential or synaptic transmission. Importantly, both pharmacological inhibition and genetic deficiency of TRPC6 almost completely abolished neuronal responses to ultrasound. Furthermore, we found that intracerebroventricular administration of a TRPC6 blocker significantly attenuated the population of neuronal firings in the cerebral cortex evoked by transcranial ultrasound irradiation in mice. Our findings indicate that TRPC6 is an indispensable molecule of ultrasound neuromodulation in the intact mammalian brains, providing fundamental understanding of biophysical molecular mechanisms of ultrasound neuromodulation as well as insight into its future feasibility in neuroscience and translational researches in humans.

DOI： 10.1101/2024.03.06.583779

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/braincomms/fcae075

症例1は68歳女性で、精神障害や神経系疾患の既往はなく、悲嘆、無関心、不安、抑うつを呈して近医を受診した。大うつ病性障害と診断され抗うつ薬を処方されたが改善はみられず、7ヵ月後に当院を紹介された。抗うつ薬を増量するも症状の改善はみられず、羞明、めまい、言語不明瞭、失行を連想させる問題行動がみられるようになり、精査の結果、前頭葉症状優位型の進行性核上性麻痺(PSP)と診断された。その後、自発行動が著明に減り、認知機能低下をきたして介護施設へ入所となった。症例2は63歳男性で、うつを呈して自殺を図り頸髄損傷を受傷した。デュロキセチンを投与されるもうつ症状の改善なく、その後に手部と脚部のしびれと疼痛、めまい、浮遊感、歩行困難、腰椎圧迫骨折をきたし、認知機能の低下が認められた。神経学的検査と画像所見からRichardson型PSPと診断を下し、さらにADLの低下、構音障害、嚥下障害を発症、診断の2年後に誤嚥性肺炎を呈して永眠された。症例3は58歳男性で、11年前に腎癌に対して手術を受け、その後にうつと不安を発症、II型双極性障害と診断され、薬物療法を受けるも軽度うつ症状は持続していた。歩行障害と振戦がみられるようになり、精査の結果、パーキンソニズム優位型PSPと診断された。レボドパ投与により一時的な症状の軽快がみられたものの、その後は徐々に悪化を呈している。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder characterized by Parkinsonism, supranuclear ophthalmoplegia, postural instability, and cognitive impairment. PATIENTS: This case series describes three patients initially diagnosed with late-life mood disorders (depression and bipolar disorder) who were later diagnosed with PSP because of the development of typical neurological symptoms. RESULT: The diagnostic challenge of PSP is highlighted in this case report, particularly in the early stages, when characteristic symptoms may not be present. The importance of considering PSP in the differential diagnosis of late-life mood disorders, especially in the absence of response to standard antidepressant therapy, is also emphasized. The heterogeneity of PSP is described, with various subtypes and atypical variants presenting with different clinical features. The psychiatric symptoms of PSP include apathy, disinhibition, depression, and anxiety, whereas hallucinations and delusions are less frequent. Tau positron emission tomography imaging is discussed as a potential biomarker for atypical PSP. CONCLUSION: Early diagnosis and intervention are crucial for improved outcomes in PSP, necessitating further research to enhance the diagnostic and treatment strategies for PSP and other neurodegenerative diseases.

DOI： 10.1002/pcn5.178

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Serotonin (5-HT) deficiency is a core biological pathology underlying depression and other psychiatric disorders whose key symptoms include decreased motivation. However, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system in macaque monkeys and quantified the effects on motivation for goal-directed actions in terms of incentives and costs. Reversible inhibition of 5-HT synthesis increased errors and reaction times on goal-directed tasks, indicating reduced motivation. Analysis found incentive-dependent and cost-dependent components of this reduction. To identify the receptor subtypes that mediate cost and incentive, we systemically administered antagonists specific to 4 major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography (PET) visualized the unique distribution of each subtype in limbic brain regions and determined the systemic dosage for antagonists that would achieve approximately 30% occupancy. Only blockade of 5-HT1A decreased motivation through changes in both expected cost and incentive; sensitivity to future workload and time delay to reward increased (cost) and reward value decreased (incentive). Blocking the 5-HT1B receptor also reduced motivation through decreased incentive, although it did not affect expected cost. These results suggest that 5-HT deficiency disrupts 2 processes, the subjective valuation of costs and rewards, via 5-HT1A and 5-HT1B receptors, thus leading to reduced motivation.

DOI： 10.1371/journal.pbio.3002445

PubMed

DOI： 10.15082/jsnt.41.3_366

CiNii Research

Presentation type：Oral presentation (general)  

Venue：愛知県大府市