Alzheimer’s disease (AD) is a progressive neurodegenerative disease with phenotypic changes closely associated with both genetic variants and imaging pathology. Brain imaging biomarker genomics has been developed in recent years to reveal... more
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with phenotypic changes closely associated with both genetic variants and imaging pathology. Brain imaging biomarker genomics has been developed in recent years to reveal potential AD pathological mechanisms and provide early diagnoses. This technique integrates multimodal imaging phenotypes with genetic data in a noninvasive and high-throughput manner. In this review, we summarize the basic analytical framework of brain imaging biomarker genomics and elucidate two main implementation scenarios of this technique in AD studies: (1) exploring novel biomarkers and seeking mutual interpretability and (2) providing a diagnosis and prognosis for AD with combined use of machine learning methods and brain imaging biomarker genomics. Importantly, we highlight the necessity of brain imaging biomarker genomics, discuss the strengths and limitations of current methods, and propose directions for development of this research field.
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Background Blood biomarkers that can be used for preclinical Alzheimer’s disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived... more
Background Blood biomarkers that can be used for preclinical Alzheimer’s disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived extracellular vesicle (nEV) cargo in patients along the Alzheimer’s continuum, focusing on cognitively normal controls (NCs) with high brain β-amyloid (Aβ) loads (Aβ+). Methods The study was based on the Sino Longitudinal Study on Cognitive Decline project. We enrolled 246 participants, including 156 NCs, 45 amnestic mild cognitive impairment (aMCI) patients, and 45 AD dementia (ADD) patients. Brain Aβ loads were determined using positron emission tomography. NCs were classified into 84 Aβ− NCs and 72 Aβ+ NCs. Baseline plasma nEVs were isolated by immunoprecipitation with an anti-CD171 antibody. After verification, their cargos, including Aβ, tau phosphorylated at threonine 181, and neurofilament light, were quantified using a single-molecule array. Concentrati...
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Introduction Subjective cognitive decline (SCD) represents a cognitively normal state but at an increased risk for developing Alzheimer’s disease (AD). Recognizing the glucose metabolic biomarkers of SCD could facilitate the location of... more
Introduction Subjective cognitive decline (SCD) represents a cognitively normal state but at an increased risk for developing Alzheimer’s disease (AD). Recognizing the glucose metabolic biomarkers of SCD could facilitate the location of areas with metabolic changes at an ultra-early stage. The objective of this study was to explore glucose metabolic biomarkers of SCD at the region of interest (ROI) level. Methods This study was based on cohorts from two tertiary medical centers, and it was part of the SILCODE project (NCT03370744). Twenty-six normal control (NC) cases and 32 SCD cases were in cohort 1; 36 NCs, 23 cases of SCD, 32 cases of amnestic mild cognitive impairment (aMCIs), 32 cases of AD dementia (ADDs), and 22 cases of dementia with Lewy bodies (DLBs) were in cohort 2. Each subject underwent [18F]fluoro-2-deoxyglucose positron emission tomography (PET) imaging and magnetic resonance imaging (MRI), and subjects from cohort 1 additionally underwent amyloid-PET scanning. The ...
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Subjective cognitive decline (SCD) is regarded as the first clinical manifestation in the Alzheimer’s disease (AD) continuum. Investigating populations with SCD is important for understanding the early pathological mechanisms of AD and... more
Subjective cognitive decline (SCD) is regarded as the first clinical manifestation in the Alzheimer’s disease (AD) continuum. Investigating populations with SCD is important for understanding the early pathological mechanisms of AD and identifying SCD-related biomarkers, which are critical for the early detection of AD. With the advent of advanced neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), accumulating evidence has revealed structural and functional brain alterations related to the symptoms of SCD. In this review, we summarize the main imaging features and key findings regarding SCD related to AD, from local and regional data to connectivity-based imaging measures, with the aim of delineating a multimodal imaging signature of SCD due to AD. Additionally, the interaction of SCD with other risk factors for dementia due to AD, such as age and the Apolipoprotein E (ApoE) ɛ4 status, has also been described. Finally, the possi...
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Research Interests: Psychology, Computer Science, Dementia, Cognition, Medicine, and 15 moreOrganization, Individuals, Brain Connectivity, Centrality, Dorsal, MCI, Degeneration, Montreal Cognitive Assessment, Cognitive Decline, resting state fMRI, Brain Network, Neurosciences, Eigenvector Centrality, Subjective Cognitive Decline, and Network Neuroscience
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The progression of Alzheimer's Disease (AD) has been proposed to comprise three stages, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. Was brain dynamics across the three stages smooth? Was there a... more
The progression of Alzheimer's Disease (AD) has been proposed to comprise three stages, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. Was brain dynamics across the three stages smooth? Was there a critical transition? How could we characterize and study functional criticality of human brain? Based on dynamical characteristics of critical transition from nonlinear dynamics, we proposed a vertex-wise Index of Functional Criticality (vIFC) of fMRI time series in this study. Using 42 SCD, 67 amnestic MCI (aMCI), 34 AD patients as well as their age-, sex-, years of education-matched 54 NC, our new method vIFC successfully detected significant patient-normal differences for SCD and aMCI, as well as significant negative correlates of vIFC in the right middle temporal gyrus with total scores of Montreal Cognitive Assessment (MoCA) in SCD. In comparison, standard deviation of fMRI time series only detected significant differences between AD patients and nor...
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The hippocampus plays important roles in memory processing. However, the hippocampus is not a homogeneous structure, which consists of several subfields. The hippocampal subfields are differently affected by many neurodegenerative... more
The hippocampus plays important roles in memory processing. However, the hippocampus is not a homogeneous structure, which consists of several subfields. The hippocampal subfields are differently affected by many neurodegenerative diseases, especially mild cognitive impairment (MCI). Amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) are the two subtypes of MCI. aMCI is characterized by episodic memory loss, and svMCI is characterized by extensive white matter hyperintensities and multiple lacunar infarctions on magnetic resonance imaging. The primary cognitive impairment in svMCI is executive function, attention, and semantic memory. Some variations or disconnections within specific large-scale brain networks have been observed in aMCI and svMCI patients. The aim of this study was to investigate abnormalities in structural covariance networks (SCNs) between hippocampal subfields and the whole cerebral cortex in aMCI and svMCI patien...
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Amnestic mild cognitive impairment (aMCI), which is recently considered as a high risk status for developing Alzheimer's disease (AD), manifests with gray matter atrophy and increased focal functional activity in the medial temporal... more
Amnestic mild cognitive impairment (aMCI), which is recently considered as a high risk status for developing Alzheimer's disease (AD), manifests with gray matter atrophy and increased focal functional activity in the medial temporal lobe (MTL). However, the abnormalities of whole-brain functional network connectivity in aMCI and its relationship to medial temporal atrophy (MTA) remain unknown. In this study, thirty-six aMCI patients and thirty-five healthy controls (HCs) were recruited. Neuropsychological assessments and MTA visual rating scaling were carried out on all participants. Furthermore, whole brain functional network was constructed at voxel level, and functional connectivity strength (FCS) was computed as the sum of the connections for each node to capture its global integrity. General linear model was used to analyze the FCS values differences between aMCI and HCs. Then, the regions showing significant FCS differences were adopted as the imaging markers for discrimin...
Research Interests: Neuroscience, Magnetic Resonance Imaging, Medicine, Multidisciplinary, Brain Mapping, and 15 moreBrain, Discriminant Analysis, Humans, Female, Amnesia, Male, PLoS one, Aged, Middle Aged, Atrophy, Functional Neuroimaging, Alzheimer Disease, Case Control Studies, Neuropsychological Tests, and Cognitive dysfunction
Changes in white matter (WM) microstructure may relate to the pathophysiology of cognitive impairment. Whether WM microstructure differs in two common pre-dementia subtypes, vascular mild cognitive impairment (VaMCI) and amnestic mild... more
Changes in white matter (WM) microstructure may relate to the pathophysiology of cognitive impairment. Whether WM microstructure differs in two common pre-dementia subtypes, vascular mild cognitive impairment (VaMCI) and amnestic mild cognitive impairment (aMCI), is largely unknown. This study included 28 VaMCI (12 men, age: 46 ~ 77 years) and 34 aMCI patients (14 men, age: 51 ~ 79 years). All patients underwent a battery of neuropsychological tests and structural and diffusion magnetic resonance imaging (MRI) scanning. WM microstructure was quantified using diffusion MRI parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD). These parameters were compared between the two patient groups using tract-based spatial statistics (TBSS) after controlling for age, gender, and education. No significant differences in FA/MD/AxD/RD were observed between the VaMCI and aMCI groups, which suggests a similar pattern of WM microstructure ...
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The ε4 allele of the Apolipoprotein E gene (APOE-ε4) is a potent genetic risk factor for sporadic Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is an intermediate state between normal cognitive aging and... more
The ε4 allele of the Apolipoprotein E gene (APOE-ε4) is a potent genetic risk factor for sporadic Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is an intermediate state between normal cognitive aging and dementia, which is easy to convert to AD dementia. It is an urgent problem in the field of cognitive neuroscience to reveal the conversion of aMCI-ε4 to AD. Based on our preliminary work, we will study the neuroimaging features in the special group of aMCI-ε4 with multi-modality magnetic resonance imaging (structural MRI, resting state-fMRI and diffusion tensor imaging) longitudinally. In this study, 200 right-handed subjects who are diagnosed as aMCI with APOE-ε4 will be recruited at the memory clinic of the Neurology Department, XuanWu Hospital, Capital Medical University, Beijing, China. All subjects will undergo the neuroimaging and neuropsychological evaluation at a 1 year-interval for 3 years. The primary outcome measures are 1) Microstructural altera...
Research Interests: Genetics, Cognitive Science, Dementia, Biomarkers, Diffusion Tensor Imaging, and 15 moreImage Analysis, China, Human, Humans, Functional Magnetic Resonance Imaging, Follow Up, Article, Apolipoprotein E, Diagnostic Imaging, Genotype, Functional Neuroimaging, Controlled Study, Disease Progression, Alzheimer Disease, and Cognitive dysfunction
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Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. We have previously reported that augmented expression of lysosome-associated membrane protein 2 (LAMP-2) was correlated with... more
Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. We have previously reported that augmented expression of lysosome-associated membrane protein 2 (LAMP-2) was correlated with the severity of PBC. This study aimed to determine whether serum LAMP-2 could serve as a predictor of biochemical response to UDCA. The efficiency of serum LAMP-2 to predict biochemical response was assessed after 1 year of UDCA treatment in PBC patients by a retrospective analysis. We found that the basal serum LAMP-2 level was increased in PBC, especially in patients with stage III-IV (p = 0.010) or TBIL > 1 mg/dL (p = 0.014). Baseline serum LAMP-2 was higher in non-responders than that in responders, but the difference was statistically insignificant. However, after UDCA treatment, serum LAMP-2 level decreased prominently in the first 3 months, which was more obvious in responders. Further studies showed that the 35% decline of LAMP-2 after t...
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Previous studies have suggested that amnestic mild cognitive impairment (aMCI) is associated with changes in cortical morphological features, such as cortical thickness, sulcal depth, surface area, gray matter volume, metric distortion,... more
Previous studies have suggested that amnestic mild cognitive impairment (aMCI) is associated with changes in cortical morphological features, such as cortical thickness, sulcal depth, surface area, gray matter volume, metric distortion, and mean curvature. These features have been proven to have specific neuropathological and genetic underpinnings. However, most studies primarily focused on mass-univariate methods, and cortical features were generally explored in isolation. Here, we used a multivariate method to characterize the complex and subtle structural changing pattern of cortical anatomy in 24 aMCI human participants and 26 normal human controls. Six cortical features were extracted for each participant, and the spatial patterns of brain abnormities in aMCI were identified by high classification weights using a support vector machine method. The classification accuracy in discriminating the two groups was 76% in the left hemisphere and 80% in the right hemisphere when all six...
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Stem cell based therapy was very attractive in decompensated liver cirrhosis currently. The possible mechanism might be due to its potential to help tissue regeneration with mini- mally invasive procedures. Here we report the case of a... more
Stem cell based therapy was very attractive in decompensated liver cirrhosis currently. The possible mechanism might be due to its potential to help tissue regeneration with mini- mally invasive procedures. Here we report the case of a 44-year-old man, infected by hepatitis B virus (HBV) combined with hepatitis C virus (HCV) for longer than 10 years, who eventu- ally developed
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Diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI) was applied for stroke diagnose in 120 acute (< 48 h) ischemic stroke patients. At hyperacute (< 6 h) stage, it is difficult to find out the infarction zone... more
Diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI) was applied for stroke diagnose in 120 acute (< 48 h) ischemic stroke patients. At hyperacute (< 6 h) stage, it is difficult to find out the infarction zone in conventional T1 or T2 image, but it is easy in DWI, apparent diffusion coefficient (ADC) map; when at 3-6-hour stage it is also easy in PWI, cerebral blood flow (CBF) map, cerebral blood volume (CBV) map, and mean transit time (MTT) map; at acute (6-48 h) stage, DWI or PWI is more sensitive than conventional T1 or T2 image too. Combining DWI with ADC, acute and chronic infarction can be distinguished. Besides, penumbra which should be developed in meaning was used as an indication or to evaluate the therapeutic efficacy. There were two cases (< 1.5 h) that broke the model of penumbra because abnormity was found in DWI but not that in PWI, finally they recovered without any sequela.
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To investigate the expression and function of classical protein kinase C (PKC) isoenzymes in inducing MDR phenotype in gastric cancer cells. Two cell lines were used in the study: gastric cancer cell SGC7901 and its drug-resistant cell... more
To investigate the expression and function of classical protein kinase C (PKC) isoenzymes in inducing MDR phenotype in gastric cancer cells. Two cell lines were used in the study: gastric cancer cell SGC7901 and its drug-resistant cell SGC7901/VCR stepwise-selected by vincristine 0.3, 0.7 and 1.0 mg.L(-1), respectively. The expression of classical PKC (cPKC) isoenzymes in SGC7901 cells and SGC7901/VCR cells were detected using immunofluorescent cytochemistry, laser confocal scanning microscope and Western blot. The effects of anti-PKC isoenzymes antibody on adriamycin accumulation in SGC7901/VCR cells were determined using flow cytometric analysis. (1)SGC7901 cells exhibited positive staining of PKC-alpha. SGC7901/VCR cells exhibited stronger staining of PKC-alpha than SGC7901 cells. The higher dosage vincristine selected, the much stronger staining of PKC-alpha was observed on SGC7901/VCR cells. (2)Both SGC7901 and SGC7901/VCR cells exhibited positive staining of PKC-beta I and PKC...
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Using a monoclonal antibody against gastric cancer antigen named MGb1 to screen a phage-displayed random peptide library fused with coat protein pIII in order to get some information on mimotopes. Through affinity enrichment and ELISA... more
Using a monoclonal antibody against gastric cancer antigen named MGb1 to screen a phage-displayed random peptide library fused with coat protein pIII in order to get some information on mimotopes. Through affinity enrichment and ELISA screening, positive clones of phages were amplified. 10 phage clones were selected after three rounds of biopanning and the ability of specific binding of the positive phage clones to MGb1-Ab were detected by ELISA assay (DNA sequencing was performed and the amino acid sequences were deduced) By blocking test, specificity of the mimic phage epitopes was identified. There were approximately 200 times of enrichment about the titer of bound phages after three rounds of biopanning procedures. DNA of 10 phage clones after the third biopanning was assayed and the result showed that the positive clones had a specific binding activity to MGb1-Ab and a weak ability of binding to control mAb or to mouse IgG. DNA sequencing of 10 phage clones was performed and th...
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To study the technique and application of perfusion weighted imaging (PWI) in the diagnosis and medical treatment of acute stroke, 25 patients were examined by 1.5 T or 1.0 T MRI scanner. The Data analysis was done with... more
To study the technique and application of perfusion weighted imaging (PWI) in the diagnosis and medical treatment of acute stroke, 25 patients were examined by 1.5 T or 1.0 T MRI scanner. The Data analysis was done with &amp;amp;quot;3D Med System&amp;amp;quot; developed by our Lab to process the data and obtain apparent diffusion coefficient (ADC) map, cerebral blood volume (CBV)
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Human mitochondrial Mrs2 protein (hsaMrs2p) is a magnesium transporter in mitochondria inner membrane. It was identified as an upregulated gene in a multidrug-resistant (MDR) gastric cancer cell line compared to its parental cells by... more
Human mitochondrial Mrs2 protein (hsaMrs2p) is a magnesium transporter in mitochondria inner membrane. It was identified as an upregulated gene in a multidrug-resistant (MDR) gastric cancer cell line compared to its parental cells by subtractive hybridization. To further explore the role of hsaMrs2p in MDR of gastric cancer cells, the cDNA encoding hsaMrs2p was generated and mouse antisera against hsaMrs2p was raised with recombinant hsaMrs2p as the immunogen. HsaMrs2p expression could positively regulate adriamycin resistance of SGC7901/ADR cells both in vitro and in vivo. Further study showed that hsaMrs2p increased adriamycin-releasing index. Its upregulation inhibited adriamycin-induced apoptosis, probably by suppressing Bax induced cytochrome C release from mitochondria. Additionally, hsaMrs2p promoted cell growth and cells with decreased hsaMrs2p exhibited significant inhibition of cell growth with G(1) cell cycle arrest. By enhanced hsaMrs2p expression, p27 was downregulated whereas cyclinD1 was upregulated. Our results provide new insights into the function of hsaMrs2p that may be a promising target for MDR reversal therapy.
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Previously, a novel protein, MGr1-Ag, was associated with tumor multidrug resistance (MDR), and the role and the underlying mechanisms of MGr1-Ag in MDR of gastric cancer cells were characterized. Initial studies using the introduction of... more
Previously, a novel protein, MGr1-Ag, was associated with tumor multidrug resistance (MDR), and the role and the underlying mechanisms of MGr1-Ag in MDR of gastric cancer cells were characterized. Initial studies using the introduction of sense or antisense vectors for MGr1-Ag resulted in the genetical up- or downregulation of MGr1-Ag in gastric cancer cells, respectively. Subsequent studies revealed the expression of MGr1-Ag, P-glycoprotein (P-gp), MDR-associated protein (MRP), Bcl-2 and Bax in gastric cancer cells via Western blot analysis. The sensitivity of gastric cancer cells to chemotherapeutic drugs was assessed using the colony-forming assay, and Adriamycin (ADM) accumulation was evaluated by flow cytometry. Further study of ADM-induced apoptosis was detected by annexin-V/propidium iodide staining. The expression level of MGr1-Ag in MDR gastric cancer cells is much higher than that in their parental cells. Overexpression of exogenous MGr1-Ag may promote the MDR phenotype of gastric cancer cells, decrease intracellular ADM accumulation and protect gastric cancer cells from ADM-induced apoptosis, whereas downregulation of MGr1-Ag had reverse effects. Western blot analysis suggested that MGr1-Ag may regulate the expression of P-gp, MRP, Bcl-2 and Bax. In conclusion, MGr1-Ag may promote MDR of gastric cancer cells via a decrease in intracellular drug accumulation and inhibition of drug-induced apoptosis.
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Research Interests: Technology, Stem Cells, Magnetic Resonance Imaging, Fluorescent Dyes and Reagents, Stem Cell, and 14 moreStem Cell Transplantation, Biological Sciences, Humans, Female, Animals, Male, Y chromosome, Experimental Study, Genetically Modified, Liver Disease, Genetic Markers, Contrast Media, Cytological Techniques, and Dynamic Range
Research Interests: Earth Sciences, Mass Spectrometry, Quality Control, Biological Sciences, Humans, and 9 moreCalibration, Male, Tandem Mass Spectrometry, High Performance Liquid Chromatography, CHEMICAL SCIENCES, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Adult, Liquid Chromatography, and Reproducibility of Results
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Research Interests: Neuroscience, Psychology, Cognitive Science, Music, Adolescent Development, and 19 moreMagnetic Resonance Imaging, Adolescent, Anisotropy, Brain, Humans, Cerebellum, Cerebral Cortex, Female, Voxel Based Morphometry, Male, Magnetic Resonance, Three Dimensional Imaging, Young Adult, White matter, Adult, Fractional Anisotropy, Neurosciences, Gray Matter, and Magnetic resonance image
Research Interests: Functional Analysis, Magnetic Resonance Imaging, Low Frequency, Neuroimmunology, Brain, and 16 moreHumans, Female, Amnesia, Neuroimage, Male, Aged, Middle Aged, Frequency Dependence, Rest, Basal ganglia, Biological clocks, Parahippocampal Gyrus, Resting State, Gray Matter, Medial Prefrontal Cortex, and Cognition disorders
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Manganese (Mn) toxicity is most often found in mining and welding industry workers. Accumulation of manganese in the brain can result in a syndrome similar to that of... more
Manganese (Mn) toxicity is most often found in mining and welding industry workers. Accumulation of manganese in the brain can result in a syndrome similar to that of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Observations on former Mn-alloy workers suggested that residual effects could last for years after exposure. The objective of this study was to assess effects of Mn in the liver of rats following subacute or subchronic exposure and after recovery. Male Sprague-Dawley rats were exposed to manganese chloride (MnCl(2)) for 30 days, 90 days, or for 90 days followed by a 30-day post-exposure recovery period. Results showed that MnCl(2) exposure resulted in liver injury in rats and the extent of injury correlated positively with exposure time. The effect in mitochondria was stronger than in the membrane or nucleus. Most of the changes in these biomarkers recovered when manganese exposure ceased.