Nai-Ching Chen

Cognitive Severity-Specific Neuronal Degenerative Network in Charcoal Burning Suicide-Related Carbon Monoxide Intoxication: A Multimodality Neuroimaging Study in Taiwan

AbstractWhile carbon monoxide (CO) intoxication often triggers multiple intraneuronal immune- or inflammatory-related cascades, it is not known whether the pathological processes within the affected regions evolve equally in the long term. To understand the neurodegenerative networks, we examined 49 patients with a clinical diagnosis of CO intoxication related to charcoal burning suicide at the chronic stage and compared them with 15 age- and sex-matched controls. Reconstructions of degenerative networks were performed using T1 magnetic resonance imaging, diffusion-tensor imaging, and fluorodeoxyglucose positron emission tomography (PET). Tract-specific fractional anisotropy (FA) quantification of 11 association fibers was performed while the clinical significance of the reconstructed structural or functional networks was determined by correlating them with the cognitive parameters. Compared with the controls, the patients had frontotemporal gray matter (GM) atrophy, diffuse white matter (WM) FA decrement, and axial diffusivity (AD) increment. The patients were further stratified into 3 groups based on the cognitive severities. The spatial extents within the frontal-insular-caudate GM as well as the prefrontal WM AD increment regions determined the cognitive severities among 3 groups. Meanwhile, the prefrontal WM FA values and PET signals also correlated significantly with the patients Mini-Mental State Examination score. Frontal hypometabolic patterns in PET analysis, even after adjusted for GM volume, were highly coherent to the GM atrophic regions, suggesting structural basis of functional alterations. Among the calculated major association bundles, only the anterior thalamic radiation FA values correlated significantly with all chosen cognitive scores. Our findings suggest that fronto-insular-caudate areas represent target degenerative network in CO intoxication. The topography that occurred at a cognitive severity-specific level at the chronic phase suggested the clinical roles of frontal areas. Although changes in FA are also diffusely distributed, different regional changes in AD suggested unequal long-term compensatory capacities among WM bundles. As such, the affected WM regions showing irreversible changes may exert adverse impacts to the interconnected GM structures.

Amyloid Burden in the Hippocampus and Default Mode Network: Relationships With Gray Matter Volume and Cognitive Performance in Mild Stage Alzheimer Disease

AbstractAmyloid load, as measured by florbetapir positron emission tomography (PET) standardized uptake value ratio (SUVr), has high specificity in the diagnosis of Alzheimer disease (AD). As the posterior cingulate cortex (PCC) represents densely amyloid-affected regions early in AD, we hypothesized that amyloid load within the key hubs of the default mode networks (DMN) may result in local or distant interconnected gray matter (GM) volume atrophy, thereby affecting cognitive performance. Thirty AD patients with a clinical dementia rating sum of box score ⩽2 were enrolled and underwent cognitive evaluation, 3-dimensional T1-weighted imaging and florbetapir PET. Volumes of interest (VOIs) included the hippocampus, lateral temporal region, and key hubs of the DMN [anterior cingulate cortex (ACC), PCC, posterior parietal, and precuneus]. The SUVr was calculated by florbetapir standard uptake value (SUV) within the T1-weighted image segmented GM VOIs divided by the cerebellar GM SUV. Our results suggested inverse correlations between ACC (&rgr; = −0.444, P = 0.016) and PCC SUVr (&rgr; = −0.443, P = 0.016) with PCC GM volume. In stepwise regression, the orientation scores were associated with PCC SUVr (&bgr; = 2.584, P = 0.02) and posterior parietal volume (&bgr; = −0.446, P = 0.04), whereas the word recall score was related to hippocampal volume (&bgr; = −0.391, P = 0.04). After removing the patients with a hippocampal VOI below the lowest tertile and adjusting for age, an inverse correlation was found between hippocampal volume and SUVr in the ACC (partial &sgr; = −0.639, P = 0.002), precuneus (partial &sgr; = −0.692, P = 0.002), and lateral temporal SUVr (partial &sgr; = −0.604, P = 0.005). Our results suggest that amyloid burden within the key DMN regions may contribute to local and distant GM atrophy, and that this may explain the cognitive scores.

Hyperhomocysteinemia in Alzheimer dementia patients and cognitive decline after 6 months follow-up period.

PURPOSE White matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are commonly found in Alzheimers disease (AD) and may contribute to cognitive impairment. Plasma total homocysteine (tHcy) had also been linked with cognitive decline in AD. We examined the relationship among change of cognition, tHcy level, and WMHs on MRI in AD patients with a follow-up periods of 6 months. METHODS AD patients with normal creatinine level and initial clinical dementia rating (CDR) of 1 to 2 were enrolled. tHcy and biochemistry tests related to cerebral vascular risk factors were collected. WMHs were measured on MRI fluid attenuated inverse recovery sequence and classified into deep white matter hyperintensities (DWMHs) and periventricular white matter hyperintensities (PWMHs) by visual rating scale. Neuropsychological tests including cognitive ability screening instrument (CASI), mini-mental state examination (MMSE) converted from CASI scores and CDR were collected twice during the follow- up period of 6 months. RESULTS Ninety-two AD patients, 30 men and 62 women completed the study while the tHcy level was not significantly different between AD and age matched controls. tHcy level showed no correlation with CASI or MMSE score, at either the first or second examination. tHcy showed positive correlation with decline of CASI total score and abstract thinking (both p<0.01) but not in MMSE decline. There was no significant correlation between neuropsychiatric assessment and WMHs, but the decline of abstract thinking score was related to frontal PWMHs (R square=0.237, p=0.007). CONCLUSION tHcy might be associated with rapid cognitive decline in AD after a 6-month follow-up period and the effect might not be directly through WMHs. tHcy level correlated with greater WMHs in the trigone area although greater lesion load by MRI was in the occipital lobe.

Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy.

Abstract Hyperammonemia has been reported to be associated with patients who receive valproic acid (VPA) therapy. This study aimed to determine the risk factors for hyperammonemia in patients with epilepsy treated with VPA. One hundred and fifty-eight adult patients with epilepsy aged older than 17 years who received VPA therapy were enrolled into this study. Blood samples were taken during the interictal state and analyzed for the blood level of ammonia. Statistical analysis was conducted between different groups of patients. The results showed that the frequency of hyperammonemia associated with VPA therapy was 27.8% (ammonia level >93 µg/dL), and 5.1% of the patients had severe hyperammonemia (ammonia level >150 µg/dL). The blood ammonia level was significantly correlated with the dosage of VPA and the plasma concentration of VPA. An increase of 1 mg in the dosage of VPA increased the risk of hyperammonemia by 0.1%. In addition, combination treatment with liver enzyme inducing antiepileptic drugs (AEDs) and antipsychotic drugs increased the risk of hyperammonemia. In conclusion, the use of VPA in adult patients with epilepsy was associated with a dose-dependent increase in blood concentrations of ammonia. Combination treatment with liver enzyme-inducing AEDs and antipsychotic drugs increased the risk of VPA-induced hyperammonemia. Most of the patients with VPA-induced hyperammonemia were asymptomatic; however, if patients taking VPA present with symptoms such as nausea, fatigue, somnolence, ataxia, and consciousness disturbance, the blood ammonia level should be measured.

Patterns of executive dysfunction in amnestic mild cognitive impairment.

BACKGROUND Executive dysfunction is not uncommon in patients with amnestic mild cognitive impairment (aMCI). This study aimed to investigate the applicability of executive function tests (EFTs) in aMCI as an aid in establishing the diagnosis of multi-domain MCI. METHODS One hundred and twenty (120) aMCI patients, 126 Alzheimers disease (AD) patients, and 100 normal controls were enrolled. The EFTs evaluated included the trail making test, digit backward span, Stroop color-word test, and design fluency and category fluency tests. RESULTS Of the aMCI participants, 66% exhibited impairment in at least one EFT. Among the five selected EFTs, the category fluency test was the most discriminative in detecting executive dysfunction between patients with aMCI (standardized β = 0.264) or AD (standardized β = 0.361) with the controls, followed by the Stroop test. The performance of aMCI patients with two or more impaired EFTs was significantly different from those of controls but not from those of AD patients. CONCLUSION In the clinical setting, aMCI patients who fail in two or more EFTs may represent a unique population with multi-domain MCI that require close follow-up.

Sleep quality and daytime sleepiness in patients with epilepsy.

PURPOSE Poor sleep quality and excessive daytime sleepiness (EDS) are common complaints of patients with epilepsy (PWE). This study aimed to evaluate possible predisposing factors for EDS and subjective sleep quality in PWE. METHODS One hundred and seventeen PWE were enrolled and 30 healthy volunteers were recruited as controls. EDS was evaluated by the Epworth Sleepiness Scale (ESS) while the Pittsburg Sleep Quality Index (PSQI) was designed to evaluate overall sleep quality. Clinical baseline data and possible risk factors for sleep disturbances were included in the statistical analysis. RESULTS Twenty percent of PWE (23/117) and 7% of healthy controls (2/30) had excessive daytime sleepiness (p = 0.007). PWE had significantly higher PSQI total scores (6.5 ± 3.8 vs. 3.7 ± 2.9), sleep latency (1.2 ± 0.8 vs. 0.6 ± 0.7) and sleep efficiency (0.8 ± 1.0 vs. 0.0 ± 0.2) scores than the controls (all p < 0.001). A significantly higher prevalence of poor sleep quality was found in the partial seizure, non-seizure-free, and polytherapy groups (all p < 0.05). Multivariate analysis showed that poor seizure control was the strongest independent risk factor for poor sleep quality (OR = 2.43, 95% CI = 1.15-5.15, p = 0.02). CONCLUSION EDS and poor sleep quality are common in PWE and are closely related to partial epilepsy, poor seizure control, and polytherapy. These relationships must be addressed in order to provide the best management of sleep disturbance in such patients.

Clinical Significance of Cerebrovascular Biomarkers and White Matter Tract Integrity in Alzheimer Disease: Clinical correlations With Neurobehavioral Data in Cross-Sectional and After 18 Months Follow-ups

AbstractCerebrovascular risk factors and white matter (WM) damage lead to worse cognitive performance in Alzheimer dementia (AD). This study investigated WM microstructure using diffusion tensor imaging in patients with mild to moderate AD and investigated specific fiber tract involvement with respect to predefined cerebrovascular risk factors and neurobehavioral data prediction cross-sectionally and after 18 months. To identify the primary pathoanatomic relationships of risk biomarkers to fiber tract integrity, we predefined 11 major association tracts and calculated tract specific fractional anisotropy (FA) values. Eighty-five patients with AD underwent neurobehavioral assessments including the minimental state examination (MMSE) and 12-item neuropsychiatric inventory twice with a 1.5-year interval to represent major outcome factors. In the cross-sectional data, total cholesterol, low-density lipoprotein, vitamin B12, and homocysteine levels correlated variably with WM FA values. After entering the biomarkers and WM FA into a regression model to predict neurobehavioral outcomes, only fiber tract FA or homocysteine level predicted the MMSE score, and fiber tract FA or age predicted the neuropsychiatric inventory total scores and subdomains of apathy, disinhibition, and aberrant motor behavior. In the follow-up neurobehavioral data, the mean global FA value predicted the MMSE and aberrant motor behavior subdomain, while age predicted the anxiety and elation subdomains. Cerebrovascular risk biomarkers may modify WM microstructural organization, while the association with fiber integrity showed greater clinical significance to the prediction of neurobehavioral outcomes both cross-sectionally and longitudinally.

Cortical metabolic and nigrostriatal abnormalities associated with clinical stage-specific dementia with Lewy bodies.

Purpose The aims of this study were to investigate the hypometabolic regions of FDG PET compared with the nigrostriatal dopamine pathway abnormalities in TRODAT-1 scan in patients with dementia with Lewy bodies (DLBs) at mild and dementia stages as well as to validate the correlation among networks being constructed with clinical data. Materials and Methods A total of 25 DLB patients were classified into 2 functional groups stratified by the Clinical Dementia Rating (CDR) Scale (CDR 0.5: n = 14, mild stage; CDR 1 or 2: n = 11, dementia stage) compared with 9 age-matched controls. Neuroimaging survey was applied using information derived from FDG PET by performing voxel-based analysis and a semiquantitative 99mTc-TRODAT-1 scan to correlate these results with the cognitive and Unified Parkinson’s Disease Rating Scale. Results Compared with normal database, the patients with mild stage showed hypometabolism in the temporal regions, anterior cingulate cortex, inferior orbital region, thalamus, and caudate nucleus. Although at the dementia stage, more extensive cortical hypometabolism involving occipital region were found. The dopamine transporter levels derived from TRODAT-1 scan had excellent discrimination in diagnosing DLB compared with age-matched normal controls (1.58 [0.2] and 1.84 [0.1], P < 0.01) but without significant differences between mild and dementia stages. The sophisticated cortical-brainstem networks by FDG PET and TRODAT-1 yielded good clinical correlation. Conclusions The networks yielded from FDG PET and TRODAT-1 revealed good correlation with clinical data and that nigrostriatal pathway abnormalities are preceded by typical occipital hypometabolism in mild stage of DLB. Dopamine transporter levels may serve as early diagnostic tool and FDG PET as staging indicator for DLB pathology.

Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer's disease.

In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism (Val66Met) that may explain individual differences in brain volume and memory-related activity. In this study, we enrolled 186 Alzheimers disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor. Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex. These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes.

Detection of gray matter damage using brain MRI and SPECT in carbon monoxide intoxication: a comparison study with neuropsychological correlation.

Purpose While lesion patterns in white matter have been extensively reported in the literature on carbon monoxide (CO) intoxication, reports on the effects on gray matter damage are less common. The aim of this study was to investigate regional damage patterns focusing on gray matter using 99mTc ethyl cysteinate dimer (ECD) brain single photon emission computed tomography (SPECT) and brain magnetic resonance imaging (MRI) with clinical correlation. Patients and Methods Thirty CO intoxication patients and 15 age-matched controls were enrolled for standard neuropsychological tests. Six regions of interest (ROI) were analyzed qualitatively and quantitatively in both SPECT and MRI. The patients were further grouped according to clinical dementia rating score. The sensitivity, specificity, and positive and negative predictive ratios related to dementia from both imaging modalities were further examined. Results In SPECT qualitative analysis, basal ganglia (n = 16) were the most common regions showing lower perfusion patterns. The basal ganglion and temporal, frontal, and parietal regions of the patients with dementia showed significantly lower perfusion patterns. MRI had a higher sensitivity while SPECT had a higher specificity and positive and negative predictive ratios in correlation with dementia among the ROI. The perfusion indices of the frontal, temporal, basal ganglion, and thalamus were inversely correlated with clinical severity (all P < 0.05). Conclusions Our findings suggest that a multiparametric neuroimaging approach may provide more information in revealing the anatomical and neurobehavioral results in patients after CO intoxication. The atrophy pattern seen in MRI may explain in part the possible mechanism of the hypoperfusion state seen in SPECT.