Gene-gene functional relationships in Alzheimer's disease: CELF1 regulates KLC1 alternative splicing.

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Severe cerebrovascular pathology of the first supercentenarian to be autopsied in the world.

We report on a 116-year-old Japanese woman who was the first officially documented supercentenarian to be autopsied in the world. She lived a remarkably healthy life until suffering cerebral infarction at 109 years of age. She became Japan's oldest person at 113 years and died in 1995 from colon cancer at 116 years 175 days. Her medical records show the delayed onset of stroke, cancer, dementia, and heart disease and the importance of appropriate medical treatment and intensive dedicated care provided during the last stage of her life. She was the longest-lived person in Japan for 21 years from 1993 until 2014. The neuropathological findings of her autopsied brain were briefly reported in the Japanese literature in 1997. In this study, we reinvestigated her brain and spinal cord in more detail. Severe cerebrovascular lesions and cervical spondylotic myelopathy were found to be the main causes of her disability. Although the density of senile plaques was relatively high, the distribution of neurofibrillary tangles was limited. Ghost tangles and argyrophilic grains were mild. The mildness of tau pathological changes in her neurons, in other words the resistance of neurons to tau pathology, may be a factor responsible for her longevity.

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43.

Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients' brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients' brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.

Macroscopic findings of brain with dementia.

In this paper, we have described the points to be noted when examining the macroscopic findings of the brain of patients with dementia. The characteristics of the macroscopic findings of the brain of patients with dementia are shown in the figure of the outer surface and the cut surface. Gross findings in the brain of patients with Alzheimer's disease should consider, in addition to the degree of limbic changes, whether the atrophy is diffuse, the degree of ventricular enlargement, and the complications of vascular changes. The macroscopic findings of the brain of patients with dementia with Lewy bodies are characterized by the absence of notable abnormal findings other than the depigmentation of the substantia nigra and locus coeruleus. In dementia with Lewy bodies, other types of dementia complications should be considered if abnormal findings are present. It should be noted that accurate diagnosis of argyrophilic grain dementia and senile dementia of neurofibrillary tangle type by macroscopic findings alone is often difficult to distinguish from a mild case of Alzheimer's disease and change by physiological aging in particular. In frontotemporal lobar degeneration, changes in the basal ganglia, brain stem, cerebellum and motor neurons should be observed to make a differential diagnosis of various types of frontotemporal lobar degeneration. It is important to understand the areas that are often damaged in different types of dementia and the extent of lesions, and to distinguish each type of dementia. Care should be taken as macroscopic findings are more complex when several types of dementia are mixed. It was shown that accurate understanding of macroscopic findings is essential for understanding clinical symptoms, imaging findings, differential diagnosis of dementia and disease pathogenesis.

Evidence for Altered Phosphoinositide Signaling-Associated Molecules in the Postmortem Prefrontal Cortex of Patients with Schizophrenia.

Phosphoinositides (PIs) play important roles in the structure and function of the brain. Associations between PIs and the pathophysiology of schizophrenia have been studied. However, the significance of the PI metabolic pathway in the pathology of schizophrenia is unknown. We examined the expression of PI signaling-associated proteins in the postmortem brain of schizophrenia patients. Protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA, also known as PIK4A), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), protein kinase B (Akt), and glycogen synthase kinase 3ß (GSK3ß) were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays of the prefrontal cortex (PFC) of postmortem samples from 23 schizophrenia patients and 47 normal controls. We also examined the association between PIK4CA expression and its genetic variants in the same brain samples. PIK4CA expression was lower, whereas Akt expression was higher, in the PFC of schizophrenia patients than in that of controls; PIP5K1C, PTEN, and GSK3ß expression was not different. No single-nucleotide polymorphism significantly affected protein expression. We identified molecules involved in the pathology of schizophrenia via this lipid metabolic pathway. These results suggest that PIK4CA is involved in the mechanism underlying the pathogenesis of schizophrenia and is a potential novel therapeutic target.

Characteristic asymmetric limbic and anterior temporal atrophy in demented patients with pathologically confirmed argyrophilic grain disease.

PURPOSE: The purpose of this study is to clarify the characteristic structural magnetic resonance imaging (MRI) findings in demented patients with pathologically confirmed argyrophilic grain disease (AGD). METHODS: Nine pathologically confirmed AGD patients with cerebral three-dimensional T1-weighted MRI were evaluated in this study. In addition to visual rating scales of atrophic and asymmetric changes in the limbic and temporal lobes, voxel-based morphometry (VBM) was performed to assess group difference between pathologically confirmed AGD and Alzheimer's disease (AD) patients. RESULTS: On visual analyses of AGD patients, the medial temporal, anterior temporal, and posterior temporal atrophy scores were 3.3 ± 0.7, 1.7 ± 0.5, and 1.0 ± 0.7, respectively. Asymmetric scores of the hippocampus and parahippocampal gyrus, amygdala and ambient gyrus, anterior temporal, and posterior temporal lobes were rated as 1.1 ± 0.7, 1.6 ± 0.5, 1.3 ± 0.8, and 0.4 ± 0.7, respectively. In spite of no statistical differences in atrophic scores, AGD patients showed the higher score and proportion of anterior temporal asymmetric score than AD (p = 0.03 and 0.02). Compared with controls, VBM analysis revealed left dominant asymmetric atrophy predominantly in the limbic and anterior temporal lobe in AGD patients. By contrast, there was no significant gray matter reduction between AGD and AD patients. CONCLUSIONS: Asymmetric atrophy relatively localized to the anterior temporal and limbic lobes including the amygdala and ambient gyrus is a characteristic MRI finding of AGD. For the precise antemortem diagnosis, especially to differentiation from AD, it is important to pay attention to this asymmetric change.

Multifaceted structural magnetic resonance imaging findings in demented patients with pathologically confirmed TDP-43 proteinopathy.

This short report clarifies the heterogeneity of structural magnetic resonance imaging (MRI) findings in seven demented patients due to pathologically accumulated TAR DNA-binding protein-43 (TDP-43) protein using visual analyses including visual rating scales (i.e., global cortical atrophy and medial temporal atrophy scales). In addition to the well-known frontotemporal lobar atrophy, structural MRI has revealed multifaceted imaging findings including asymmetric atrophy of the frontoparietal lobe and cerebral peduncle, midbrain atrophy, and localized or diffuse white matter T2 hyperintensity. Understanding of these multifaceted neuroimaging findings is important for the precise antemortem diagnosis of TDP-43 proteinopathy.

Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism.

We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth-Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.

Factors influencing hospital admission among patients with autopsy-confirmed dementia.

BACKGROUND: The symptoms of geriatric syndromes and the behavioural and psychological symptoms of dementia (BPSD), in addition to clinical conditions, are associated with hospital admission among dementia patients. However, the principal factors that necessitate hospital admission among dementia patients have not been fully elucidated. METHODS: We retrospectively reviewed the data in the medical and autopsy reports of patients who had been treated at a hospital in Toyohashi, Japan. Each patient had been hospitalized sometime between 2012 and 2016 and underwent a brain autopsy. Dementia and the subtypes of dementia were diagnosed neuropathologically. Information about patients' general backgrounds, clinical conditions at the time of admission, and the geriatric syndrome symptoms and BPSD before admission was collected; comparisons were then made between patients with and without dementia and among those with the different major subtypes of dementia. Then, the factors relating to hospital admission of dementia patients were comprehensively evaluated by using principle component analysis. RESULTS: Of the 128 eligible patients, 100 (78.1%) had dementia. In the comparison of patients with and without dementia, patients without dementia were younger at both admission (P = 0.034) and death (P = 0.003). Among the patients with dementia with Lewy bodies, delusions had a significantly high prevalence (P = 0.014). Principal component analysis identified nine components (disinhibition, irritability/lability, agitation/aggression, anxiety, delusions, sleep/night-time behaviour disorders, hallucinations, aberrant motor behaviour, and speech impairment) as the principal factors related to hospital admission among dementia patients. Thus, BPSD were identified as principal factors. CONCLUSIONS: Compared to other factors, BPSD are more likely to cause dementia patients to be admitted to hospital. The present results indicate that measures should be taken to ameliorate the difficulties associated with caring for patients with BPSD at home.

[Effects of drug treatment on the surviral-time in patients with dementia].

AIM: The effect of polypharmacy on the surviral-time in patients with dementia has never been fully elucidated. METHODS: A retrospective study was conducted in a hospital in Aichi, Japan, by reviewing the medical charts and autopsy reports. Patients were hospitalized and neuropathologically diagnosed with dementia. The data on medication was collected from the prescribed drugs taking right before the admission. Patients were divided into two groups according to the number of prescribed drugs: ≥ 5 drugs (polypharmacy) vs. ≤ 4 drugs (non-polypharmacy). "Drugs to be prescribed with special caution" were defined in accordance with the guidelines for medical treatment and its safety in the elderly (2015). RESULTS: Seventy-six patients were eligible, and 39.5% of patients had polypharmacy. The Kaplan-Meier method showed that the polypharmacy group tended to have a shorter survival-time than the non-polypharmacy group (p=0.067). A Cox proportional hazard model showed that the polypharmacy group tended to have a higher risk for a reduced survival-time than the non-polypharmacy group, and this tendency was more prominent after adjusting for sex and age at admission (adjusted hazard ratio, 1.631; 95% confidence interval, 0.991-2.683; p=0.054). "Drugs to be prescribed with special caution", including hypnotic-sedative drugs, antianxiety drugs, antipsychotics, and benzodiazepines, were not found to be risk factors for a reduced survival-time. CONCLUSIONS: The present study showed that polypharmacy in terminal patients with dementia tended to carry a risk for reducing their remaining lifespan. The results warrant further additional study.

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-ß accumulation in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-ß (Aß) in human brain is still not well understood. To identify novel genes that cause accumulation of Aß in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aß level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aß accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.

Complement Activation in Capillary Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is classified as type 1 with capillary amyloid ß (Aß) or type 2 without capillary Aß. While it is known that CAA activates complement, an inflammatory mediator, there is no information on the relationship between capillary Aß and complement activation. METHODS: We evaluated 34 autopsy brains, including 22 with CAA and 12 with other neurodegenerative diseases. We assessed the vascular density of CAA by analyzing the expression of complement (C1q, C3d, C6, C5b-9), macrophage scavenger receptor (MSR), and apolipoprotein E (ApoE). RESULTS: Capillary immunostaining for C1q, C3d, MSR, and ApoE was identified almost exclusively in CAA-type1 brains. There was intense expression of C1q, C3d, MSR, and ApoE, as well as weaker expression of C5b-9 and C6 in the arteries/ arterioles of both CAA subtypes, but not in control brains. C5b-9 and C6 were preferentially expressed in arteries/arterioles with subcortical hemorrhage or cortical superficial siderosis. Triple immunofluorescence revealed that C1q, C3d, and ApoE were colocalized with Aß in CAA brain capillaries. CONCLUSION: Complement, MSR, and ApoE were only coexpressed in the presence of Aß accumulation in capillaries, suggesting a role for complement activation in the propagation of Aß. Additionally, C5b-9 expression may be associated with hemorrhagic brain injury in CAA.

Beyond the midbrain atrophy: wide spectrum of structural MRI finding in cases of pathologically proven progressive supranuclear palsy.

PURPOSE: Recently, it has been recognized that pathologically proven progressive supranuclear palsy (PSP) cases are classified into various clinical subtypes with non-uniform symptoms and imaging findings. This article reviews essential imaging findings, general information, and advanced magnetic resonance imaging (MRI) techniques for PSP and presents these MRI findings of pathologically proven typical and atypical PSP cases for educational purposes. METHODS: With the review of literatures, notably including atypical pathologically proven PSP cases, MRI and clinical information of 15 pathologically proven typical and atypical PSP cases were retrospectively evaluated. RESULTS: In addition to typical symptoms, PSP patients can exhibit atypical symptoms including levodopa-responsive parkinsonism, pure akinesia, non-fluent aphasia, corticobasal syndrome, and predominant cerebellar ataxia. As well as clinical symptoms, the degree of midbrain atrophy, a well-known imaging hallmark, is not consistent in atypical PSP cases. This fact has important implications for the limitation of midbrain atrophy as a diagnostic imaging biomarker of PSP pathology. Additional evaluation of other imaging findings including various regional atrophies of the globus pallidus, frontal lobe, cerebral peduncle, and superior cerebellar peduncle is essential for the diagnosis of atypical PSP cases. CONCLUSION: It is necessary for radiologists to recognize the wide clinical and radiological spectra of typical and atypical PSP cases.

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-ß accumulation modifier.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of Aß accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aß accumulation. To avoid detecting secondarily affected genes by Aß, we used non-Tg mice in the absence of Aß pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an Aß modifier, indicating a role for intracellular trafficking in Aß accumulation. Aß levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of Aß, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aß pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.

Simultaneous determination of post-translational racemization and isomerization of N-terminal amyloid-ß in Alzheimer's brain tissues by covalent chiral derivatized ultraperformance liquid chromatography tandem mass spectrometry.

Typical markers of protein aging are spontaneous post-translational modifications such as amino acid racemization (AAR) and amino acid isomerization (AAI) during the degradation of peptides. The post-translational AAR and AAI could significantly induce the density and localization of plaque deposition in brain tissues. Alzheimer's disease (AD) is reliably related to the formation and aggregation of amyloid-ß peptide (Aß) plaques in the human brain. No current analytical methods can simultaneously determine AAR and AAI during the degradation of Aß from AD patients. We now report a covalent chiral derivatized ultraperformance liquid chromatography tandem mass spectrometry (CCD-UPLC-MS/MS) method for the determination of post-translational AAR and AAI of N-terminal Aß (N-Aß1-5) in human brain tissues. When subjected to tryptic N-Aß1-5 from post-translationally modified natural Aß in focal brain tissues by the CCD procedure, it was monitored at m/z 989.6→637.0/678.9 during electrospray collision-induced dissociation. These N-Aß1-5 fragments with l-aspartic acid (l-Asp), d-Asp, l-isoAsp, and d-isoAsp could be separated using the UPLC system with a conventional reversed-phase column and mobile phase. The quantification of these peptides was determined using a stable isotope [(15)N]-labeled Aß1-40 internal standard. The CCD-UPLC-MS/MS assay of potential N-Aß1-5 allowed for the discovery of the present and ratio levels of these N-Aß1-5 sequences with l-Asp, d-Asp, l-isoAsp, and d-isoAsp.

Voxel-based Morphometry of Alzheimer's Disease Using a Localizer Image: A Comparative Study with Magnetization Prepared Rapid Acquisition with Gradient Echo.

PURPOSE: Magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequence is a gold-standard technique for voxel-based morphometry (VBM) because of high spatial resolution and excellent tissue contrast, especially between gray matter (GM) and white matter (WM). Despite its benefits, MPRAGE exhibits distinct challenge for VBM in some patients with neurological disease because of long scan time and motion artifacts. Speedily acquired localizer images may alleviate this problem. This study aimed to evaluate the feasibility of VBM using 3D Fast Low Angle Shot image captured for localizer (L3DFLASH). METHODS: Consecutive 13 patients with pathologically confirmed Alzheimer's disease (AD) (82 ± 9 years) and 21 healthy controls (HC) (79 ± 4 years) were included in this study. Whole-brain L3DFLASH and MPRAGE were captured and preprocessed using the Computational Anatomy Toolbox 12 (CAT12). Agreement with MPRAGE was evaluated for L3DFLASH using regional normalized volume for segmented brain areas. In addition to brain volume difference on VBM and Bland-Altman analysis, atrophic pattern of AD on VBM was evaluated using L3DFLASH and MPRAGE. RESULTS: Acquisition time was 18 s for L3DFLASH and 288 s for MPRAGE. There was a slight systematic difference in all regional normalized volumes from L3DFLASH and MPRAGE. For the whole cohort, GM volume measured from MPRAGE was greater than that from L3DFLASH in most of the region on VBM. When AD and HC were compared, AD-related atrophic pattern was demonstrated in both L3DFLASH and MPRAGE on VBM, although the difference was noted in significant clusters between them. CONCLUSION: Although systematic difference was noted in regional brain volume measured from L3DFLASH and MPRAGE, AD-related atrophic pattern was preserved in L3DFLASH on VBM. VBM, using speedily acquired localizer image, may provide limited but useful information for evaluating brain atrophy.

The influence of limbic-predominant age-related TDP-43 encephalopathy on argyrophilic grain disease: A voxel-based morphometry analysis of pathologically confirmed cases.

BACKGROUND: The influence of limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathological change (LATE-NC) on structural alterations in argyrophilic grain disease (AGD) have not been documented. This study aimed to investigate the morphological impact of LATE-NC on AGD through voxel-based morphometry (VBM) technique. MATERIALS AND METHODS: Fifteen individuals with pathologically verified AGD, comprising 6 with LATE-NC (comorbid AGD [cAGD]) and 9 without LATE-NC (pure AGD [pAGD]), along with 10 healthy controls (HC) were enrolled. Whole-brain 3D-T1-weighted images were captured and preprocessed utilizing the Computational Anatomy Toolbox 12. VBM was employed to compare gray matter volume among (i) pAGD and HC, (ii) cAGD and HC, and (iii) pAGD and cAGD. RESULTS: In comparison to HC, the pAGD group exhibited slightly asymmetric gray matter volume loss, particularly in the ambient gyrus, amygdala, hippocampus, anterior cingulate gyrus, and insula. Alternatively, the cAGD group exhibited greater gray matter volume loss, with a predominant focus on the inferolateral regions encompassing the ambient gyrus, amygdala, hippocampus, and the inferior temporal area, including the anterior temporal pole. The atrophy of the bilateral anterior temporal pole and right inferior temporal gyrus persisted when contrasting the pAGD and cAGD groups. CONCLUSION: Comorbidity with LATE-NC is linked to different atrophic distribution, particularly affecting the inferolateral regions in AGD. Consequently, the consideration of comorbid LATE-NC is crucial in individuals with AGD exhibiting more widespread temporal atrophy.

Marked alteration of phosphoinositide signaling-associated molecules in postmortem prefrontal cortex with bipolar disorder.

AIM: The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3ß (GSK3ß), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. METHODS: The protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3ß were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3ß, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. RESULTS: PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3ß were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. CONCLUSION: Our results suggest that the expression levels of Akt1/GSK3ß and its upstream regulator PTEN are considerably altered.