Xiaomei Zhong

CSF levels of the neuronal injury biomarker visinin-like protein-1 in Alzheimer's disease and dementia with Lewy bodies.

The overlapping clinical features of Alzheimers disease (AD) and Dementia with Lewy bodies (DLB) make differentiation difficult in the clinical environment. Evaluating the CSF levels of biomarkers in AD and DLB patients could facilitate clinical diagnosis. CSF Visinin‐like protein‐1 (VILIP‐1), a calcium‐mediated neuronal injury biomarker, has been described as a novel biomarker for AD. The aim of this study was to investigate the diagnostic utility of CSF VILIP‐1 and VILIP‐1/Aβ1–42 ratio to distinguish AD from DLB. Levels of CSF VILIP‐1, t‐tau, p‐tau181P, Aβ1–42, and α‐synuclein were measured in 61 AD patients, 32 DLB patients, and 40 normal controls using commercial ELISA kits. The results showed that the CSF VILIP‐1 level had significantly increased in AD patients compared with both normal controls and DLB patients. The CSF VILIP‐1 and VILIP‐1/Aβ1–42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. Additionally, CSF VILIP‐1 levels were positively correlated with t‐tau and p‐tau181P within each group and with α‐synuclein in the AD and control groups. We conclude that CSF VILIP‐1 could be a diagnostic marker for AD, differentiating it from DLB. The analysis of biomarkers, representing different neuropathologies, is an important approach reflecting the heterogeneous features of AD and DLB.

Alterations of CSF Cystatin C Levels and Their Correlations with CSF Αβ40 and Αβ42 Levels in Patients with Alzheimer's Disease, Dementia with Lewy Bodies and the Atrophic Form of General Paresis

Immunohistochemical studies have revealed that cystatin C (CysC) co-localizes with amyloid-β (Αβ) in amyloid-laden vascular walls and in the senile plaque cores of amyloid. In vitro and in vivo animal studies suggest that CysC protects against neurodegeneration by inhibition of cysteine proteases, inhibition of Αβ aggregation, induction of autophagy and induction of cell division. CysC levels may be altered and may have a potential link with cerebrospinal fluid (CSF) Aβ levels in various types of dementia with characteristic amyloid deposits, such as Alzheimers disease (AD), dementia with Lewy bodies (DLB) and the atrophic form of general paresis (AF-GP). We assessed the serum and CSF levels of CysC and the CSF levels of Aβ40 and Aβ42 in patients with AD (n = 51), DLB (n = 26) and AF-GP (n = 43) and normal controls (n = 30). Using these samples, we explored the correlation between CSF CysC and CSF Aβ levels. We found that in comparison to the normal control group, both CSF CysC and CSF Aβ42 levels were significantly lower in all three dementia groups (all p<0.001); serum CysC levels were the same in the AD and DLB groups, and were lower in the AF-GP group (p = 0.008). The CSF CysC levels were positively correlated with both the CSF Aβ40 and Aβ42 levels in the AD, AF-GP and normal control groups (r = 0.306∼0.657, all p<0.05). Lower CSF CysC levels might be a common feature in dementia with characteristic amyloid deposits. Our results provide evidence for the potential role of CysC involvement in Aβ metabolism and suggest that modulation of the CysC level in the brain might produce a disease-modifying effect in dementia with characteristic amyloid deposits.

Discriminative analysis of schizophrenia using support vector machine and recursive feature elimination on structural MRI images.

AbstractStructural abnormalities in schizophrenia (SZ) patients have been well documented with structural magnetic resonance imaging (MRI) data using voxel-based morphometry (VBM) and region of interest (ROI) analyses. However, these analyses can only detect group-wise differences and thus, have a poor predictive value for individuals. In the present study, we applied a machine learning method that combined support vector machine (SVM) with recursive feature elimination (RFE) to discriminate SZ patients from normal controls (NCs) using their structural MRI data. We first employed both VBM and ROI analyses to compare gray matter volume (GMV) and white matter volume (WMV) between 41 SZ patients and 42 age- and sex-matched NCs. The method of SVM combined with RFE was used to discriminate SZ patients from NCs using significant between-group differences in both GMV and WMV as input features. We found that SZ patients showed GM and WM abnormalities in several brain structures primarily involved in the emotion, memory, and visual systems. An SVM with a RFE classifier using the significant structural abnormalities identified by the VBM analysis as input features achieved the best performance (an accuracy of 88.4%, a sensitivity of 91.9%, and a specificity of 84.4%) in the discriminative analyses of SZ patients. These results suggested that distinct neuroanatomical profiles associated with SZ patients might provide a potential biomarker for disease diagnosis, and machine-learning methods can reveal neurobiological mechanisms in psychiatric diseases.

1H-Proton Magnetic Resonance Spectroscopy Differentiates Dementia with Lewy Bodies from Alzheimer's Disease

FDG-PET and SPECT studies suggest that hypometabolism and hypoperfusion in occipital lobe and posterior cingulate gyrus (PCG) are prominent features of dementia with Lewy bodies (DLB) and Alzheimers disease (AD), respectively. Cerebral blood flow and glucose metabolism are tightly linked to brain energy metabolism. 1H-MRS is a useful tool to directly detect energy metabolism. We aimed to use 1H-MRS to characterize metabolite concentrations in the occipital lobe and PCG in DLB and AD patients, and estimate their usefulness in the diagnosis of DLB. Nineteen DLB, 21 AD, and 18 normal control (NC) subjects underwent 1H-MRS with the voxels placed in bilateral occipital lobes and left PCG. The N-acetylaspartate (NAA) and glutamate (Glu) concentrations in occipital lobe in DLB were lower than those in AD and NC. Concentrations of these two metabolites in PCG in DLB were lower than those in NC, and were the same as those in AD. These results remained robust after correcting for relative gray matter volume in the region of interest. The NAA and Glu concentrations in occipital lobe in DLB were found correlated with global cognitive function. From the ROC curves with Glu concentrations in occipital lobe, the mean areas under the curve were 0.845 for the DLB/control (with sensitivity 83.3% and specificity 84.2%) and 0.773 for the DLB/AD (with sensitivity 66.7% and specificity 84.2%). Our study suggests that 1H-MRS investigation is valuable to detect the characteristic patterns of metabolite concentrations and is helpful in the diagnostic process and assessing dementia severity in DLB.

Different cerebrospinal fluid levels of Alzheimer-type biomarker Aβ42 between general paresis and asymptomatic neurosyphilis

Neurosyphilis is a neurological disease that involves infection of the central nervous system with Treponema pallidum. With increases in unsafe sexual behaviour, syphilis has re‐emerged worldwide. To explore the amyloid and tau metabolism in neurosyphilis patients in different stages, the levels of Alzheimer‐type biomarkers in general paresis (GP) and asymptomatic neurosyphilis (ANS) patients in comparison to patients with Alzheimers disease (AD) and normal controls (NCs) were investigated.

Neuropsychiatric Features of Neurosyphilis: Frequency, Relationship with the Severity of Cognitive Impairment and Comparison with Alzheimer Disease

Background: The pattern of neuropsychiatric features of patients with neurosyphilis and the impact of the severity of cognitive impairment on neuropsychiatric syndromes are unknown. Objective: We aim to assess the neuropsychiatric features of patients with neurosyphilis, and compare the impact of the severity of cognitive impairment on the neuropsychiatric syndromes between neurosyphilis and Alzheimer disease (AD). Methods: Neuropsychiatric symptoms and the degree of cognitive impairment were assessed in a case-control study of 91 neurosyphilis, 162 AD, 157 mild cognitive impairment, and 139 normal controls by the Neuropsychiatric Inventory (NPI) scale and Clinical Dementia Rating scale, respectively. Factor analysis was performed on the 12 NPI items. Results: Factor analysis showed that patients with neurosyphilis showed more severe neuropsychiatric syndromes at the dementia stage than those neurosyphilis patients at the mild cognitive impairment stage, while neuropsychiatric manifestations were equally common among the different stages of dementia (all p < 0.05). Frontal lobe syndrome was more severe in patients with neurosyphilis than in patients with AD from the early mild cognitive impairment stage to the moderate dementia stage (all p < 0.01). Conclusions: Patients with neurosyphilis show different patterns of neuropsychiatric syndromes at the mild cognitive impairment and dementia stages, and differ from patients with AD.

Cognitive Impairment and Structural Abnormalities in Late Life Depression with Olfactory Identification Impairment: an Alzheimer’s Disease-Like Pattern

Abstract Background Late-life depression patients are at a high risk of developing Alzheimer’s disease, and diminished olfactory identification is an indicator in early screening for Alzheimer’s disease in the elderly. However, whether diminished olfactory identification is associated with risk of developing Alzheimer’s disease in late-life depression patients remains unclear. Methods One hundred and twenty-five late-life depression patients, 50 Alzheimer’s disease patients, and 60 normal controls were continuously recruited. The participants underwent a clinical evaluation, olfactory test, neuropsychological assessment, and neuroimaging assessment. Results The olfactory identification impairment in late-life depression patients was milder than that in Alzheimer’s disease patients. Diminished olfactory identification was significantly correlated with worse cognitive performance (global function, memory language, executive function, and attention) and reduced grey matter volume (olfactory bulb and hippocampus) in the late-life depression patients. According to a multiple linear regression analysis, olfactory identification was significantly associated with the memory scores in late-life depression group (B=1.623, P<.001). The late-life depression with olfactory identification impairment group had worse cognitive performance (global, memory, language, and executive function) and more structural abnormalities in Alzheimer’s disease-related regions than the late-life depression without olfactory identification impairment group, and global cognitive function and logical memory in the late-life depression without olfactory identification impairment group was intact. Reduced volume observed in many areas (hippocampus, precuneus, etc.) in the Alzheimer’s disease group was also observed in late-life depression with olfactory identification impairment group but not in the late-life depression without olfactory identification impairment group. Conclusion The patterns of cognitive impairment and structural abnormalities in late-life depression with olfactory identification impairment patients were similar to those in Alzheimer’s disease; olfactory identification may help identify late-life depression patients who are at a high risk of developing Alzheimer’s disease.

Weight Rich-Club Analysis in the White Matter Network of Late-Life Depression with Memory Deficits

Patients with late-life depression (LLD) have a higher incident of developing dementia, especially individuals with memory deficits. However, little is known about the white matter characteristics of LLD with memory deficits (LLD-MD) in the human connectome, especially for the rich-club coefficient, which is an indicator that describes the organization pattern of hub in the network. To address this question, diffusion tensor imaging of 69 participants [15 LLD-MD patients; 24 patients with LLD with intact memory (LLD-IM); and 30 healthy controls (HC)] was applied to construct a brain network for each individual. A full-scale battery of neuropsychological tests were used for grouping, and evaluating executive function, processing speed and memory. Rich-club analysis and global network properties were utilized to describe the topological features in each group. Network-based statistics (NBS) were calculated to identify the impaired subnetwork in the LLD-MD group relative to that in the LLD-IM group. We found that compared with HC participants, patients with LLD (LLD-MD and LLD-IM) had relatively impaired rich-club organizations and rich-club connectivity. In addition, LLD-MD group exhibited lower feeder and local connective average strength than LLD-IM group. Furthermore, global network properties, such as the shortest path length, connective strength, efficiency and fault tolerant efficiency, were significantly decreased in the LLD-MD group relative to those in the LLD-IM and HC groups. According to NBS analysis, a subnetwork, including right cognitive control network (CCN) and corticostriatal circuits, were disrupted in LLD-MD patients. In conclusion, the disease effects of LLD were prevalent in rich-club organization. Feeder and local connections, especially in the subnetwork including right CCN and corticostriatal circuits, were further impaired in those with memory deficits. Global network properties were disrupted in LLD-MD patients relative to those in LLD-IM patients.

Kynurenine pathway changes in late-life depression with memory deficit

Kynurenine pathway (KP) activation is associated with many neuropsychiatric diseases, such as major depressive disorder (MDD) and Alzheimers disease (AD). Investigations conducted on MDD seldom shed light on KP changes in late-life depression (LLD), though memory deficit (MD) in patients with LLD is a predictable sign of AD. Thus, we aimed to investigate whether tryptophan (TRP) metabolism and kynurenine (KYN) metabolism were imbalanced in patients with LLD with MD and in patients with LLD without MD. We explored KP characteristics between LLD with MD and LLD without MD groups. We investigated 85 patients with LLD and MD, 71 patients with LLD without MD, and 129 healthy controls (HCs). Serum concentrations of TRP, KYN, and kynurenic acid (KYNA) were detected by liquid chromatography-tandem mass spectrometry. Cognition performance was assessed by the Mini-Mental State Examination (MMSE). Language ability was assessed by the Boston Naming Test (BNT). Depressive symptoms were assessed by the 17-item Hamilton Depression Scale (HAMD-17). Lower TRP and KYNA levels, a lower KYNA/KYN ratio and a higher KYN/TRP ratio were found in patients with LLD and MD compared to those in HC. Low levels of TRP and KYN, in the absence of a changed KYN/TRP ratio, were found in patients with LLD without MD. The KYNA/TRP ratio and MMSE, BNT, and HAMD-17 scores were associated with the presence of LLD. MMSE scores and a trend for the KYN/TRP ratio were associated with the presence of MD in patients with LLD. Aside from MMSE scores, there was a trend toward an association between the KYN/TRP ratio and the presence of MD in patients with LLD. In conclusion, profound shifts in TRP metabolism and KYN metabolism were found in patients with LLD and MD but not in patients with LLD without MD.

Negative bias in expression-related mismatch negativity(MMN) in remitted late-life depression: An event-related potential study

Negative bias in cognition is closely associated with susceptibility to recurrent episodes of depression. Given the high recurrence rate of depression, previous studies have focused on the attentive level in late-life depression (LLD), but depression relapse is difficult to detect as a lower chief complaint in elderly people. Facial expression mismatch negativity (EMMN) is a tool that can measure cognitive bias in pre-attentive processing. In this study, we sought to explore the cognitive bias in pre-attentive emotional information processing in LLD. Thirty patients with remitted LLD and 30 non-depressed, age- and gender-matched normal controls (NC) were enrolled in this study. Automatic emotional processing was elicited by using an expression-related oddball paradigm in all participants. There were no significant differences in N170 amplitude and latency between remitted LLD and NC. Compared with NC subjects, patients with remitted LLD demonstrated an attenuated mean amplitude of positive and negative EMMN, whereas the mean amplitude of negative EMMN in remitted LLD was much larger than that of positive EMMN. Our findings suggest that although basic processing of facial expressions is intact in remitted LLD, automatic processing of facial expressions in remitted LLD is impaired with a negative bias in cognition. Further investigation of the contributions of negative bias in EMMN to susceptibility to recurrence of LLD is warranted.