Association Between Blood Biochemical Factors Contributing to Cognitive Decline and B Vitamins in Patients With Alzheimer's Disease.

Background: Malnutrition, metabolism stress, inflammation, peripheral organs dysfunction, and B vitamins deficiency significantly contribute to the progression and mortality of Alzheimer's disease (AD). However, it is unclear which blood biochemical indicators are most closely related to cognitive decline and B vitamins deficiency (thiamine, folate, vitamin B12) in patients with AD. Methods: This was a cross-sectional study of 206 AD patients recruited from six hospitals in China. Thiamine diphosphate (TDP), the bioactive form of thiamine, was measured by high-performance liquid chromatography fluoroscopy (HPLC) at a single center. Levels of biochemical indicators (except TDP) were measured by regular and standard laboratory tests in each hospital. Pearson's rank correlation analysis was used to assess relationships between B vitamins and biochemical indicators. T-test was used to compare the difference between ApoE ε4 and non-ApoE ε4 groups. Differences were considered statistically significant as P < 0.05. Results: Among the biochemical results, in AD population, malnutrition indicators (erythrocyte, hemoglobin, serum albumin, and total protein) were most significantly associated with cognitive function, as was free triiodothyronine (FT3) levels which had been observed in previous study. Malnutrition and FT3 levels depend on age but not apolipoprotein E (ApoE) genotype. Meanwhile, Among the B vitamins, TDP was the most significantly associated with malnutrition indicators and FT3. Conclusion: Our results indicated that TDP reduction could be a modifiable risk factor for malnutrition and FT3 that contributed to cognitive decline in AD patients. Correcting thiamine metabolism could serve as an optional therapy target for AD treatment.

Substantia nigra integrity correlates with sequential working memory in Parkinson's disease.

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson's disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HC, 18 women). In neuromelanin-sensitive structural MRI, PD patients showed smaller SN than HC. In a digit ordering task with functional MRI, participants either recalled sequential digits in the original order ('pure recall') or rearranged the digits and recalled the new sequence ('reorder & recall'). PD patients performed less accurately than HC, accompanied by the caudate and pallidal hypo-activation, subthalamic hyper-activation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with larger SN tended to exhibit smaller ordering-related accuracy costs ('reorder & recall' versus 'pure recall'). This effect was fully mediated by the ordering-related caudate activation. Unlike HC, the ordering-related accuracy cost correlated with the ordering-related caudate activation but not subthalamic activation in PD. Moreover, the ordering-related caudate activation correlated with the SN area but not the daily dose of D2/3 receptor agonists. In PD, the daily dose of D2/3 receptor agonists correlated with the ordering-related subthalamic activation, which was not related to the accuracy cost. The findings suggest that damage to the SN may lead to sequential working memory deficits in PD, mediated by basal ganglia dysfunction.SIGNIFICANCELiu et al. demonstrate that damage to the substantia nigra (SN) correlates with basal ganglia dysfunction and poor sequencing performance in Parkinson's disease (PD). In neuromelanin-sensitive MRI, PD showed smaller SN than healthy controls. In a digit ordering task with functional MRI, PD's lower task accuracy was accompanied by the caudate and pallidal hypo-activation, subthalamic hyper-activation, and weakened functional connectivity between the SN and basal ganglia. PD with larger SN exhibited greater ordering-related caudate activation and lower ordering-related accuracy cost when sequencing digits. PD with more daily exposure to D2/3 receptor agonists exhibited greater ordering-related subthalamic activation, which did not reduce accuracy cost. It suggests that the SN may affect sequencing performance by regulating the task-dependent caudate activation in PD.

A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status.

BACKGROUND: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer's disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. METHODS: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. RESULTS: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015). CONCLUSION: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

Visual quality and performance following bilateral implantation of TECNIS Symfony intraocular lenses with or without micro-monovision.

Purpose: To evaluate the visual quality and performance of TECNIS Symfony intraocular lenses (IOLs) implanted with or without micro-monovision approach. Setting: Chongqing Aier Mega Eye Hospital, Chongqing, China; Daping Hospital of Army Medical University, Chongqing, China. Design: Prospective study. Methods: The study comprised 70 cataract patients who had bilateral implantation of TECNIS Symfony extended range of vision IOLs, either with intended micro-monovision (monovision group: 35 patients) or with intended emmetropia (control group: 35 patients). Visual acuity, modulation transfer function (MTF), defocus curve, spectacle independence, and photic phenomena were analyzed 3 months postoperatively. Results: There was no significant difference between the two groups in binocular uncorrected visual acuity at distance. Mean binocular uncorrected visual acuity at intermediate (monovision: 0.81 dec; control: 0.58 dec) and near (monovision: 0.59 dec; control: 0.30 dec) were significantly better in the monovision group. In the monovision group, the difference of MTF values between the dominant and the non-dominant eyes was not statistically significant and MTF values were within the normal range for both eyes. Spectacle independence at intermediate and near was statistically significantly higher in the monovision group compared to the control group. The incidence of photic phenomena was similar in both groups. Conclusion: Micro-monovision implantation of TECNIS Symfony IOLs provided a superior range of visual acuity from far to near and higher spectacle independence compared to a control group targeted for emmetropia.

Mild cognitive impairment in de novo Parkinson's disease: A neuromelanin MRI study in locus coeruleus.

BACKGROUND: We aimed to investigate neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in the locus coeruleus of de novo Parkinson's disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment. METHODS: Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast-to-noise ratio of the locus coeruleus in the neuromelanin-sensitive MRI images and cortical thickness were measured. RESULTS: The contrast-to-noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast-to-noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast-to-noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson's Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness. CONCLUSIONS: Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus-norepinephrine system might be targeted for early-intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society.

Decreased Function of Delayed Recall in Non-demented Elderly Subjects With Apolipoprotein E ε4 Allele.

Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Inconsistent results about the role of APOE ε4 alleles on cognitive decline of community non-dementia elderly have been reported. This study aimed to examine the relationship between APOE ε4 allele and cognitive abilities in the subjects aged 60 years or above from a community in Shanghai, China. A total of 1445 participants voluntarily accepted the analysis of APOE genotype and global cognitive assay using the Mini Mental Status Evaluation (MMSE). There were no significant differences in total MMSE scores between APOE ε4 carriers and non-carriers. In addition, the performances of orientation, registration, attention, calculation, and language had no significant differences between subjects with and without APOE ε4 allele. However, stratified analysis showed that the performance of delayed recall in subjects with APOE ε4 allele was inferior to that in non-ε4 carriers (p = 0.041). Further, the multiple linear regression analysis showed the significant correlations between the presence of APOE ε4 allele and the scores of the delayed memory subdomain if age, gender, and education were adjusted but no significant correlations if the related factors were not adjusted. The results indicate that significant impact of APOE ε4 allele only on the delay memory but not on global or other sub-domains of cognitive abilities.

Combined Visualization of Nigrosome-1 and Neuromelanin in the Substantia Nigra Using 3T MRI for the Differential Diagnosis of Essential Tremor and de novo Parkinson's Disease.

Differentiating early-stage Parkinson's disease (PD) from essential tremor (ET) remains challenging. In the current study, we aimed to evaluate whether visual analyses of neuromelanin-sensitive magnetic resonance imaging (NM-MRI) combined with nigrosome-1 (N1) imaging using quantitative susceptibility mapping (QSM) in the substantia nigra (SN) are of diagnostic value in the differentiation of de novo PD from untreated ET. Sixty-eight patients with de novo PD, 25 patients with untreated ET, and 34 control participants underwent NM-MRI and QSM. NM and N1 signals in the SN on MR images were visually evaluated using a 3-point ordinal scale. Receiver operating characteristic (ROC) analyses were performed to determine the diagnostic values of the visual ratings of NM and N1. The diagnostic values of the predicted probabilities were calculated via logistic regression analysis using the combination of NM and N1 visual ratings, as well as their quadratic items. The proportions of invisible NM and invisible N1 were significantly higher in the PD group than those in the ET and control groups (p < 0.001). The sensitivity/specificity for differentiating PD from ET was 0.882/0.800 for NM and 0.794/0.920 for N1, respectively. Combining the two biomarkers, the area under the curve (AUC) of the predicted probabilities was 0.935, and the sensitivity/specificity was 0.853/0.920 when the cutoff value was set to 0.704. Our findings demonstrate that visual analyses combing NM and N1 imaging in the SN may aid in differential diagnosis of PD and ET. Furthermore, our results suggest that patients with PD exhibit larger iron deposits in the SN than those with ET.

Neuromelanin-sensitive MRI of the substantia nigra: An imaging biomarker to differentiate essential tremor from tremor-dominant Parkinson's disease.

INTRODUCTION: We aimed to evaluate whether neuromelanin-sensitive MRI (NM-MRI) features in the substantia nigra pars compacta (SNc) were of diagnostic value to differentiate untreated essential tremor (ET) from de novo tremor-dominant Parkinson's disease (PDT). METHODS: Eighteen untreated ET patients, 21 de novo PDT patients and 21 healthy control subjects were recruited. All the subjects underwent clinical examination, motor and cognitive evaluations, as well as NM-MRI. High signal intensity of the lateral, central and medial SNc subregions on NM-MRI were evaluated using the width, signal intensity (contrast-to-noise ratio, CNR) and visual analysis. Diagnostic test performance of SNc values was investigated by using receiver operating characteristic analysis and net reclassification improvement (NRI). RESULTS: The width and CNR values of the lateral and central SNc subregions in PDT were significantly decreased compared with those in ET and control group. Using visual analysis, the total visual score of all SNc subregions was significantly reduced in PDT when compared with ET and control group. The width of the lateral SNc subregion allowed the best differentiation between ET and PDT, and visual analysis also showed good diagnostic value. NRI result indicated that visual analysis and the width of the lateral SNc subregion had the same diagnostic power. CONCLUSIONS: The neuromelanin changes of SNc in ET and PDT follow the different patterns. Both the measurements and visual analysis of SNc on NM-MRI provide high diagnostic accuracy for differentiating ET from PDT subtype. NM-MRI is a potential tool in diagnostic work-up of tremor disorders.

Elevated microRNA-520d-5p in the serum of patients with Parkinson's disease, possibly through regulation of cereloplasmin expression.

Iron metabolism dysfunction and redox-active iron-induced oxidative stress in the brain may contribute to the pathogenesis of Parkinson's disease. We have previously demonstrated that reduced serum ceruloplasmin level exacerbates nigral iron deposition in Parkinson's disease, although the underlying cause of the low serum ceruloplasmin level in Parkinson's disease remains unknown. Fluorescent quantitative real-time polymerase chain reaction analysis revealed that patients with Parkinson's disease had higher serum levels of microRNA (miR)-520d-5p than controls (p = 0.0011). Patients with Alzheimer's disease or multiple system atrophy did not have significantly elevated miR-520d-5p levels. Expression of miR-520d-5p did not correlate with disease severity or the motor phenotype of Parkinson's disease. Luciferase assays confirmed that miR-520d-5p was associated with ceruloplasmin gene expression, as predicted by the TargetScan tool and miRBase. In vitro experiments showed that miR-520d-5p reduced ceruloplasmin gene expression in the U251 astrocyte cell line. Our data suggest that miR-520d-5p may be a potential regulator of ceruloplasmin gene expression in vitro.

High thiamine diphosphate level as a protective factor for Alzheimer's disease.

Objectives Thiamine diphosphate (TDP) is an indispensable coenzyme for three key enzymes in glucose metabolism. Reduced TDP levels in patients with Alzheimer's disease (AD) has been widely demonstrated and is a diagnostic biomarker for the disease. In this study, we further explored the correlation between altered TDP metabolism and AD along with other risk factors. Methods A 1:1 case-control study was employed with 90 AD patients and 90 control subjects with normal-range cognitive abilities as assayed by the Mini Mental Status Evaluation. Age (≤2 years variation), gender, and educational background were strictly matched. Levels of the main thiamine metabolites in whole blood samples, including TDP, thiamine monophosphate, and thiamine, were assayed using high-performance liquid chromatography. Apolipoprotein E genotypes, haemoglobin, and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol) associated with AD were also measured. Results The odds ratio of TDP level for AD was 0.95 (with TDP level as a continuous variable) or 0.09 (with TDP level as a dichotomized variable with a cut-off value of 99.48 nmol/L). Blood TDP levels were significantly decreased in female AD patients compared to male AD patients. No correlations were identified between TDP levels and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol). Conclusions TDP is a protective factor for AD and its protective efficacy may be independent of other metabolic factors. The difference of TDP levels between genders may be another possible explanation for the higher prevalence of AD in females.

Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not.

BACKGROUND: The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer's disease (AD), remains elusive. METHODS: Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[18F]fluoro-2-deoxy-D-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-ß (Aß) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection. RESULTS: FDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aß deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency. CONCLUSIONS: We demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction.

Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson's disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

Measurement of Blood Thiamine Metabolites for Alzheimer's Disease Diagnosis.

BACKGROUND: Brain glucose hypometabolism is an invariant feature and has significant diagnostic value for Alzheimer's disease. Thiamine diphosphate (TDP) is a critical coenzyme for glucose metabolism and significantly reduced in brain and blood samples of patients with Alzheimer's disease (AD). AIMS: To explore the diagnostic value of the measurement of blood thiamine metabolites for AD. METHODS: Blood TDP, thiamine monophosphate, and thiamine levels were detected using high performance liquid chromatography (HPLC). The study included the exploration and validation phases. In the exploration phase, the samples of 338 control subjects and 43 AD patients were utilized to establish the models for AD diagnosis assayed by receiver operating characteristic (ROC) curve, including the variable γ that represents the best combination of thiamine metabolites and age to predict the possibility of AD. In the validation phase, the values of models were further tested for AD diagnosis using samples of 861 control subjects, 81 AD patients, 70 vascular dementia patients, and 13 frontotemporal dementia patients. RESULTS: TDP and the γ exhibited significant and consistent values for AD diagnosis in both exploration and validation phases. TDP had 0.843 and 0.837 of the areas under ROC curve (AUCs), 77.4% and 81.5% of sensitivities, and 78.1% and 77.2% of specificities respectively in the exploration and validation phases. The γ had 0.938 and 0.910 of AUCs, 81.4% and 80.2% of sensitivities, and 90.5% and 87.2% of specificities respectively in the exploration and validation phases. TDP and the γ can effectively distinguish AD from vascular dementia (64.3% for TDP, 67.1% for γ) and frontotemporal dementia (84.6% for TDP, 100.0% for γ). Interpretation. The measurement of blood thiamine metabolites by HPLC is an ideal diagnostic test for AD with inexpensive, easy to perform, noninvasive merits.

Correlation of thiamine metabolite levels with cognitive function in the non-demented elderly.

Thiamine metabolism is critical for glucose metabolism and also vital for brain function, which is susceptible to decline in the elderly. This study aimed to investigate whether thiamine metabolites correlate with cognitive function in the non-demented elderly and their impact factors. Volunteers >60 years old were recruited and their blood thiamine metabolites and Mini-Mental State Examination (MMSE) scores were measured. The apolipoprotein E (APOE) genotype, routine blood parameters, liver and kidney function, and levels of fasting blood glucose and triglycerides were also measured. The results showed that the thiamine diphosphate (TDP) level weakly correlated with MMSE score in the non-demented elderly. Participants with high TDP levels performed better in Recall and Attention and Calculation than those with low TDP. TDP levels were associated with the APOE ε2 allele, body mass index, hemoglobin level, fasting blood glucose, and triglycerides. Our results suggest that TDP, which is easily affected by many factors, impacts cognitive function in the elderly.

[Transplantation of human embryonic neural stem cells protects rats against cerebral ischemic injury].

The purpose of this study is to explore the fate and effect of human embryonic neural stem cells (hNSCs) after transplantation into ipsilateral lateral ventricle of stroke rats. Adult rats were exposed to one-hour transient middle cerebral artery occlusion (MCAO), and then hNSCs were transplanted into ipsilateral lateral ventricle 7 days after reperfusion. Infarct volume was calculated by cresyl violet staining. The improvements of neural functions were assessed by behavioral tests. Immunofluorescence staining was performed to observe the migration and differentiation of transplanted hNSCs. The results showed that transplanted hNSCs significantly reduced ischemia-induced infarction in MCAO rats, and improved neural functional restoration when assessed by rotarod, footfault and corner-turn tests. The grafted cells migrated predominantly to several specific brain regions, such as corpus callosum and peri-infarct area. Furthermore, these cells differentiated into oligodendrocytes and astrocytes in corpus callosum, and neurons in peri-infarct parenchyma. These results suggest that transplanted hNSCs through lateral ventricle of the ischemic side may exert effective therapeutic effects on stroke rats via migration and differentiation in specific brain regions.

Neurotrophic Signaling Factors in Brain Ischemia/Reperfusion Rats: Differential Modulation Pattern between Single-Time and Multiple Electroacupuncture Stimulation.

Electroacupuncture (EA) treatment has been widely used for stroke-like disorders in traditional Chinese medicine. However, the underlying mechanisms remain unclear. Our previous studies showed that single-time EA stimulation at "Baihui" (GV 20) and "Shuigou" (GV 26) after the onset of ischemia can protect the brain against ischemic injury in rats with middle cerebral artery occlusion (MCAO). Here, we further investigated the differential effects between multiple EA and single-time EA stimulation on ischemic injury. In the present study, we found that both single-time EA and multiple EA stimulation significantly reduced MCAO-induced ischemic infarction, while only multiple EA attenuated sensorimotor dysfunctions. Also, with PCR array screening and ingenuity gene analysis, we revealed that multiple EA and single-time EA stimulation could differentially induce expression changes in neurotrophic signaling related genes. Meanwhile, with western blotting, we demonstrated that the level of glia maturation factor ß (GMFß) increased in the early stage (day 1) of reperfusion, and this upregulation was suppressed only by single-time EA stimulation. These findings suggest that the short-term effect of single-time EA stimulation differs from the cumulative effect of multiple EA, which possibly depends on their differential modulation on neurotrophic signaling molecules expression.