Wen-Neng Chang

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.

Cerebrotendinous Xanthomatosis Patients With and Without Parkinsonism: Clinical Characteristics and Neuroimaging Findings

Parkinsonism in cerebrotendinous xanthomatosis (CTX) is rare. There are no published studies with imaging findings of dopamine transporter using 99mTc‐[2‐[[2‐[[[3‐(4‐chlorophenyl)‐8‐methyl‐8‐azabicyclo [3,2,1] oct‐2‐yl] methyl] (2‐mercaptoethyl) amino] ethyl] amino]‐ethanethiolato(3‐)‐N2,N2,S2,S2]oxo‐[1R‐(exo‐exo)] (99mTc‐TRODAT‐1) SPECT in CTX patients. This report is on the clinical details of five genetically‐proven CTX patients (two with and three without parkinsonism). Imaging findings using cranial magnetic resonance (MR) imaging and 99mTc‐TRODAT‐1 SPECT are also shown. Clinical correlation of neuroimaging findings and clinical presentations was made. A literature review of the clinical and neuroimaging features of eight CTX patients with parkinsonism reported in the English literature is also presented. The parkinsonian features of our two cases and the other eight reported cases occurred before the age of 50 years. The MR imaging study showed variable findings, in which, besides the common diffuse cerebral and cerebellar white matter lesions shown in CTX, several focal brain lesions were also noted. Of the focal lesions, substantia nigra abnormalities were seen only in the two cases with parkinsonism. The 99mTc‐TRODAT‐1 SPECT study showed different degrees of unilateral or bilateral abnormalities in the striatal binding in both visual and semiquantitative assessments. parkinsonism can be one of the neurologic presentations of CTX. Even though abnormal findings of the substantia nigra were detected in both of our CTX patients with parkinsonism, basal ganglion lesions have not been uniformly described in MR imaging findings of reported CTX patients with parkinsonism. 99mTc‐TRODAT‐1 SPECT study can be of value in the detection of striatal involvement, and the study results also suggest pre‐synaptic dopamine neuron involvement in CTX patients with parkinsonism.

Clinical significance of the pallidoreticular pathway in patients with carbon monoxide intoxication

Whereas globus pallidus lesions resulting from carbon monoxide intoxication have been extensively described in the literature, the clinical significance of pallidoreticular lesions has rarely been mentioned. This study incorporated information from functional and structural imaging to explore the correlations of pallidoreticular lesions with parkinsonian features and neurobehavioural performance. Twenty-five patients (11 males) with globus pallidus lesions after carbon monoxide intoxication and 25 age- and sex-matched controls were enrolled for detailed neurological examinations, cognitive testing, susceptibility weighted imaging, diffusion tensor imaging and 99mTc-TRODAT-1 single photon emission computed tomography. The post-processing analysis of the neuroimaging included voxel-based morphometry to assess the regional atrophy, tract-based spatial statistics related to white matter involvement, tractography to investigate the rostral and caudal projections from the midbrain level and specific uptake ratios of 99mTc-TRODAT-1 for presynaptic dopaminergic transporter activity. In susceptibility weighted imaging, low-intensity pallidoreticular lesions were detected from the minimal-intensity projections, which were visible in only 7.7% of the T(1)-weighted images and 15.4% of the T(2)-weighted images, whereas inhomogeneous intensities were detected in the globus pallidus. The patients were further divided into two subgroups based on the presence (n = 13) or absence (n = 12) of pallidoreticular lesions. The patients with pallidoreticular lesions showed increased parkinsonian features, poorer performances on the neuropsychiatric tests, lower 99mTc-TRODAT-1 availability in both the caudate and the putamen and greater atrophy of the thalamus, posterior corpus callosum, cerebral peduncle and white matter surrounding the globus pallidus compared to those without pallidoreticular lesions. The tractography results obtained with seed regions of interest in the substantia nigra showed rostral projections to the supplementary motor cortex and anterior cingulate cortex via the globus pallidus; the two pathways were distinct but ran in parallel, caudal to the level of the globus pallidus. In conclusion, the presence of pallidoreticular lesions after carbon monoxide intoxication indicates a poorer cognitive state, which is associated with extensive grey and white matter damage in addition to the damage to the nigra-striatal neuronal networks. The presence of parkinsonian features may be related to pallidal and presynaptic dopaminergic dysfunction. The sensitivity for detecting pallidoreticular lesions can be greatly improved by using susceptibility weighted imaging compared with conventional imaging.

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;u200a=u200a−0.444, Pu200a=u200a0.016) and PCC SUVr (&rgr;u200a=u200a−0.443, Pu200a=u200a0.016) with PCC GM volume. In stepwise regression, the orientation scores were associated with PCC SUVr (&bgr;u200a=u200a2.584, Pu200a=u200a0.02) and posterior parietal volume (&bgr;u200a=u200a−0.446, Pu200a=u200a0.04), whereas the word recall score was related to hippocampal volume (&bgr;u200a=u200a−0.391, Pu200a=u200a0.04). 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;u200a=u200a−0.639, Pu200a=u200a0.002), precuneus (partial &sgr;u200a=u200a−0.692, Pu200a=u200a0.002), and lateral temporal SUVr (partial &sgr;u200a=u200a−0.604, Pu200a=u200a0.005). 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.

PURPOSEnWhite 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.nnnMETHODSnAD 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.nnnRESULTSnNinety-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).nnnCONCLUSIONntHcy 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 >93u2009µg/dL), and 5.1% of the patients had severe hyperammonemia (ammonia level >150u2009µg/dL). The blood ammonia level was significantly correlated with the dosage of VPA and the plasma concentration of VPA. An increase of 1u2009mg 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.

Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare genetic disorder. Recent studies show that brain damage in CTX patients extends beyond the abnormalities observed on conventional magnetic resonance imaging (MRI). We studied the MRI and 99 mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) findings of CTX patients and made a correlation with the neuropsychological presentations.MethodsDiffusion tensor imaging (DTI) and 3D T1-weighted images of five CTX patients were compared with 15 age-matched controls. Voxel-based morphometry (VBM) was use to delineate gray matter (GM) and white matter (WM) volume loss. Fractional anisotropy (FA), mean diffusivity (MD), and eigenvalues derived from DTI were used to detect WM changes and correlate with neuropsychological results. SPECT functional studies were used to correlate with GM changes.ResultsCognitive results showed that aside from moderate mental retardation, the patient group performed worse in all cognitive domains. Despite the extensive GM atrophy pattern, the cerebellum, peri-Sylvian regions and parietal-occipital regions were correlated with SPECT results. WM atrophy located in the peri-dentate and left cerebral peduncle areas corresponded with changes in diffusion measures, while axial and radial diffusivity suggested both demyelinating and axonal changes. Changes in FA and MD were preceded by VBM in the corpus callosum and corona radiata. Cognitive results correlated with FA changes.ConclusionIn CTX, GM atrophy affected the perfusion patterns. Changes in WM included atrophy, and axonal changes with demyelination. Disconnection of major fiber tracts among different cortical regions may contribute to cognitive impairment.

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.

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.

Tc99m-sestamibi thigh SPECT/CT images for noninvasive assessment of skeletal muscle injury in carbon monoxide intoxication with clinical and pathological correlation.

Purpose: Muscle weakness has been repeatedly reported in patients with carbon monoxide (CO) intoxication. In animal models, CO intoxication has been linked with mitochondrial electron transport dysfunction. The objectives of the present study were to use Tc-99m sestamibi thigh single-photon emission computed tomography/computed tomography (SPECT/CT) to evaluate the mitochondrial status in patients with CO intoxication, correlate this with clinical parameters, and compare with age-matched controls. Material and Methods: A total of 25 patients with delayed sequelae after CO intoxication (range: 1–60 months) and 17 sex- and age-matched healthy volunteers underwent Tc-99m sestamibi thigh SPECT/CT. Cognitive evaluation and muscle power according to medical research council (MRC) grading were collected. Both visual scoring from planar images and automatic volumetric analysis were used to rate the Tc-99m sestamibi uptake level. Results: The visual scores showed that 14 patients (56.0%) were scored as moderate-to-severe decrement. Volumetric analysis showed that a significant Tc99m-sestamibi uptake decrement was found in the CO intoxication group as compared with the controls, and 16 patients (64.0%) had uptakes below 1 standard deviation of the control group. In the CO group, the muscle power but not the cognitive evaluation correlated with Tc-99m sestamibi uptake in muscles. The decrement of muscle Tc99m-sestamibi uptake was related to mitochondria swelling, increased mitochondrial numbers, and type II muscle atrophy in 1 patient. Conclusions: In this study, we demonstrated that patients with CO intoxication sustained defective mitochondrial metabolism in skeletal muscles as revealed by a decrement in Tc-99m sestamibi uptake either by visual or semiquantification of thigh SPECT/CT. Tc-99m sestamibi scanning provided noninvasive measurement of mitochondrial injury in muscles after CO intoxication and the correlation with clinical parameters was good.