Studies on the mechanism of Panax Ginseng in the treatment of deficiency of vital energy dementia rats based on urine metabolomics.

Panax Ginseng (PG) has been used to strengthen memory and physique for thousands of years, because its main components ginsenosides (GS) and ginseng polysaccharides (GP) play a major role, but its mechanism is not clear. In this study, a rat model of dementia with vital energy deficiency (DED) was established through intraperitoneal injection with D-galactose and AlCl3 and combined with exhaustive swimming. Pharmacological studies and the urine metabolomics based on ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were employed for evaluation the efficacy of PG and exploring this treatment mechanism. Through urine metabolic profiling, it can be seen that DED rats after PG administration are close to normal group (NG) rats, and PG can regulate the in vivo status of DED rats which tend to NG. The results of behavioral, biochemical indicators and immunohistochemistry further verified the above results, and the mechanism of action of each component is refined. Ultimately, we believe that the mechanism of PG in the treatment of DED is that ginsenosides (GS) intervenes in phenylalanine tryptophan and tyrosine metabolism, stimulates dopamine production, inhibits Aß deposition and neuroinflammation; and that ginseng polysaccharides (GP) provides energy to strengthen the TCA cycle and improve immune capacity.

Hydrophilic interaction chromatography combined with ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction for determination of underivatized neurotransmitters in dementia patients' urine samples.

A sensitive, rapid, precise and specific analytical method of hydrophilic interaction ultra-performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry (HILIC-UHPLC-QTRAP®/MS2) combined with a high-efficiency and easy sample preparation technology of ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction (UA-IL-DLLME) was developed to investigate neurotransmitters (NTs) in mild cognitive impairment, mild dementia and moderate dementia patients' urine samples. Firstly, the UA-IL-DLLME parameters were optimized using Plackett-Burman screening and rotatable central composite design, and the main optimal conditions were obtained: ultrasound power of 307 W, ultrasound time of 4.3 min and agitation time of 4.8 min. Secondly, HILIC-UHPLC-QTRAP®/MS2 method was developed to simultaneously determine 15 underivatized NTs in urine samples. The analysis results of clinical samples showed that some NTs such as γ-aminobutyric acid (GABA), acetylcholine (Ach) and glutamic acid (Glu) presented significant differences in different dementia stages. Finally, multivariate analysis based on the combination of principal component analysis and supervised counter propagation artificial neural network was developed for comprehensive analysis of the obtained clinical data sets. As a result, GABA and Glu were simultaneously presented meaningful contribution for classification of samples, and might be considered as potential differential compounds to the urine samples from cluster patients with different dementia stages. In summary, the presented strategy of preparation, analysis and statistics might be used to investigate NTs in different clinical biological fluids.

Effects of Dietary Taurine Supplementation on Blood and Urine Taurine Concentrations in the Elderly Women with Dementia.

The purpose of this research is to investigate the effects of dietary taurine supplementation on blood and urine taurine concentrations of the elderly women with dementia. Subjects were 31 female elderly with dementia hospitalized in a geriatric hospital. They were divided randomly into control group and dietary taurine supplemented group. Basically, same meals were served to both groups. Scorched rice water without taurine were served to control group. Scorched rice water containing 3 g of taurine were reserved to taurine group with lunch similarly. Food ingredients containing high concentration of taurine were eliminated from the meal menu. Blood and urine samples were obtained from each subject at the beginning of study, after 2 week and 4 weeks in the morning fasting state. Taurine concentrations in serum and urine were measured as taurine-fluorescamine derivatives using high performance liquid chromatography (HPLC). Data were analyzed using SPSS 20.0. The average taurine concentrations in serum and urine of subjects were 89.2 ± 9.5 µM and 876.7 ± 97.1 µM at the beginning. After 4 weeks, the taurine concentrations in serum and urine of dietary taurine supplemented group were 218.0 ± 15.6 µM and 6502.6 ± 380.6 µM, which were significantly higher compared to control group. Dietary taurine supplemented group showed positive changes in the score on language and execute performance. So taurine supplementation can provide beneficial effects to the elderly and the elderly with dementia.

Comparison of Urinary Excretion of Taurine Between Elderly with Dementia and Normal Elderly.

The purpose of this study was to investigate the differences in dietary intake, serum level and urinary excretion of taurine between the elderly with dementia and the normal elderly. Subjects with dementia were 22 (8 men, 14 women) and normal were 26 (2 men, 24 women). The general characteristics, anthropometric data were considered together. The blood and urine samples were obtained from the elderly in the morning fasting state. Taurine concentrations in serum and urinary excretion were determined using high performance liquid chromatography (HPLC). Dietary intake data were collected using questionnaires, and analyzed by Computer Aided Nutritional analysis program (CAN-pro 4.0). Statistical analyses were carried out using SPSS 20.0. There were no significant differences in age and BMI (body mass index) between the elderly with dementia and the normal elderly, however, blood total cholesterol, LDL cholesterol and HDL cholesterol levels of the elderly with dementia were relatively higher than the normal elderly. The elderly men with dementia took more lipid, riboflavin higher than the normal elderly men (P < 0.05). The elderly women with dementia took more nutrients except vitamin D, vitamin B12 and taurine than the normal elderly (P < 0.001). There were slight differences in serum taurine level between the two groups. However, urinary excretion of taurine in the elderly with dementia was significantly higher than the normal elderly (41.2%, P < 0.05).

The risk of dementia with the use of 5 alpha reductase inhibitors.

INTRODUCTION: There has been considerable interest in the interplay between testosterone and cognition. Dihydrotestosterone (DHT), which has been correlated with cognitive function, is significantly reduced with the use of 5 alpha reductase inhibitors (5ARI) for prostatic enlargement. Our objective was to assess whether the use of 5ARIs was associated with an increased risk of incident dementia. METHODS: We used a matched cohort design and linked administrative data from the province of Ontario, Canada. A total of 99 covariates were measured, and a propensity score was used for matching; 81,162 men who used a 5ARIs were matched to an equal number of men who did not. RESULTS: New initiation of 5ARI medication was associated with an increased risk of dementia during the first (HR 2.18, 95% CI 2.01-2.35) and second (HR 1.52, 95% CI 1.39-1.67) year, however this risk was nonsignificant among the men with the longest exposure to 5ARIs (HR 1.06, 95% CI 0.98-1.14). There was no difference in the results between types of 5ARIs. CONCLUSION: As the strength of the association decreased with increased exposure, the higher risk seen in the initial two years likely represents the presentation and treatment of urinary symptoms which coexist with mild cognitive impairment and eventually progresses to a diagnosis of dementia.

Evaluation of dementia by acrolein, amyloid-ß and creatinine.

Plasma, urine and cerebrospinal fluid (CSF) were examined for biochemical markers of dementia. Protein-conjugated acrolein (PC-Acro) and the amyloid-ß (Aß)40/42 ratio in plasma can be used to detect mild cognitive impairment (MCI) and Alzheimer's disease (AD). In plasma, PC-Acro and the Aß40/42 ratio in MCI and AD were significantly higher relative to non-demented subjects. Furthermore, urine acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA)/creatinine (Cre) and amino acid-conjugated acrolein (AC-Acro)/Cre in AD were significantly lower than MCI. It was also shown that reduced urine 3-HPMA/Cre correlated with increased plasma Aß40/42 ratio in dementia. The Aß40/PC-Acro ratio in CSF, together with Aß40 and Aß40/42 ratio, was lower in AD than MCI. Increased plasma PC-Acro and Aß40/42 ratio and decreased urine 3-HPMA/Cre correlated with cognitive ability (MMSE). These results indicate that the measurements of acrolein derivatives together with Aß and Cre in biologic fluids is useful to estimate severity of dementia.

Nerve growth factor receptors in dementia.

BACKGROUND/AIM: Nerve growth factor (NGF) promotes the survival and differentiation of sensory and sympathetic neurons. Several studies have found that certain neuropathological factors stimulate NGF receptor expression and release the truncated nerve growth factor receptor (TNGFR) to biological fluids. The aim of this pilot study was to determine urine TNGFR levels in patients with dementia and to verify whether TNGFR can be used as a biomarker of dementia. MATERIALS AND METHODS: Twelve patients with dementia and 12 healthy individuals were asked to voluntarily participate in this study. Ages, sexes, and weights were matched. The first morning urine samples were collected and the concentrations of TNGFR in the urine samples were measured by fluoroimmunoassay. RESULTS: The mean levels of TNGFR in the urine samples of the healthy control subjects and the patients with dementia were 164 ± 23 and 341 ± 66 ng / mg creatinine respectively. A positive relationship was found between the levels of TNGFR in different ages of both control and patient subgroups. This is consistent with the previous observations that pathological condition may stimulate the NGF receptor expression. CONCLUSION: These findings might be of assistance to evaluate the development of the memory loss associated with Alzheimer disease and other age-associated diseases.

[Anti-dementia effect of Tongluo Xingnao effervescent tablet based on urinary metabonomics].

Tongluo Xingnao effervescent tablet (TLXNET) is a patented prescription, which comes from modified Xionggui decoction and can improve cognitive function. However, its effect on the urine metabolites and anti-dementia mechanism in the dementia model rats induced by hippocampal injection with Aß25-35 remains unclear. The experiment focused on the changes in trajectory and inter-relationship among the urinary metabolite of rats in the blank group, Aß25-35 hippocampal injection dementia model group and the TLXNET intervention group, in order to determine theirs characteristic metabolic markers and explain the anti-dementia effect of TLX-NET base on the change of metabolic trajectory of these bio-markers. According to the experimental results, 5, 6-indolequinone, 4-hydroxyphenyl pyruvic acid (4-HPPA), cortisol and 3-thiosulfate lactic were preliminarily identified as the characteristic metabolic markers. They mainly participate in dopamine system, glucocorticoids and energy metabolic pathways. TLXNET can apparently downregulate the disturbances of metabolic trajectory of the four bio-markers. The experiment indicates that the dementia model induced by injecting Aß25-3 into hippocampus has its characteristic endogenous metabolic markers in urine, and ELXNET can ameliorate dementia by down-regulating the disturbances of metabolic trajectory.

Biomarkers in dementia: clinical utility and new directions.

Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic.

Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk.

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment. OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [≥ 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk. SETTING: The Cardiovascular Health Cognition Study. PATIENTS: Three thousand, one-hundred six participants (mean age, ∼ 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098). MAIN OUTCOME MEASURE: Incident hip fracture. RESULTS: There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk. CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

Relationship between longitudinal measures of renal function and onset of dementia in a community cohort of older adults.

OBJECTIVES: To evaluate the association between dynamic measures of renal function ascertained over time and onset of dementia. DESIGN: Prospective community cohort study. SETTING: Group Health, Seattle, Washington. PARTICIPANTS: Two thousand nine hundred sixty-eight adults aged 65 and older followed for the development of dementia over a median of 6.0 years (interquartile range 3.1-10.1 years). MEASUREMENTS: Time-varying measures of renal function were constructed based on 49,340 serum creatinine measurements and included average estimated glomerular filtration rate (eGFR), eGFR trajectory, and variability in eGFR around this trajectory over 5-year exposure windows. The association between these three eGFR exposure measures and risk of dementia was estimated using a Cox regression model adjusted for other participant characteristics. Time-varying measures of urine protein by dipstick were also adjusted for in sensitivity analyses. RESULTS: Participants with a lower eGFR had a higher incidence of dementia, but this did not reach statistical significance in adjusted analyses (omnibus P = .14). There were trends toward a higher adjusted incidence of dementia in participants with positive eGFR trajectories (omnibus P = .07) and greater variability in eGFR (omnibus P = .04) over time. The results of sensitivity analyses, including those in which time-varying measures of proteinuria were included, were consistent with those of the primary analysis. CONCLUSION: In a community cohort of older adults followed for a median of 6 years, strong associations were not found between measures of kidney disease severity and progression and incident dementia.

Urinary excretion of 8-oxo-7,8-dihydroguanine as biomarker of oxidative damage to DNA.

Oxidatively damaged DNA may be important in carcinogenesis. 8-Oxo-7,8-dihydroguanine (8-oxoGua) is an abundant and mutagenic lesion excised by oxoguanine DNA glycosylase 1 (OGG1) and measurable in urine or plasma by chromatographic methods with electrochemical or mass spectrometric detectors, reflecting the rate of damage in steady state. A common genetic OGG1 variant may affect the activity and was associated with increased levels of oxidized purines in leukocytes without apparent effect on 8-oxoGua excretion or major change in cancer risk. 8-OxoGua excretion has been associated with exposure to air pollution, toxic metals, tobacco smoke and low plasma antioxidant levels, whereas fruit and vegetable intake or dietary interventions showed no association. In rodent studies some types of feed may be source of 8-oxoGua in collected urine. Of cancer therapies, cisplatin increased 8-oxoGua excretion, whereas radiotherapy only showed such effects in experimental animals. Case-control studies found high excretion of 8-oxoGua in relation to cancer, dementia and celiac disease but not hemochromatosis, although associations could be a consequence rather than reflecting causality of disease. One prospective study found increased risk of developing lung cancer among non-smokers associated with high excretion of 8-oxoGua. Urinary excretion of 8-oxoGua is a promising biomarker of oxidatively damaged DNA.

Chronic kidney disease, cognitive decline, and incident dementia: the 3C Study.

OBJECTIVE: To evaluate the longitudinal relationship between moderate chronic kidney disease (CKD), decline in kidney function, and microalbuminuria with subsequent cognitive decline and incident dementia. METHODS: This study is based on a population-based cohort of 7,839 subjects over 65 years with 7 years of follow-up. Glomerular filtration rate was estimated (eGFR) using the CKD-EPI equation. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) and dementia was actively screened and diagnosed. RESULTS: At baseline, 12% of the participants had an eGFR <60 mL/min/1.73 m(2). A total of 564 incident dementia cases were diagnosed during the follow-up. Low baseline eGFR values were not associated with an increased risk of incident dementia or cognitive decline over the 7-year follow-up, except a borderline significant association with dementia with vascular component. However, eGFR decline over the first 4-year period was associated with higher risk of dementia with vascular component (relative risk = 5.35 [1.76-16.3] in those with eGFR decline >4 mL/min/1.73 m(2)/y compared with those <4) and with higher cognitive decline on the MMSE (-0.12 points, p < 0.01 in those with eGFR >4 mL/min/1.73 m(2)/y compared with those <4) in the 3 subsequent years. Proteinuria tended to be associated with an increased risk of subsequent dementia with vascular component. CONCLUSIONS: Despite a large sample and a long follow-up, we found no increased risk of cognitive decline or dementia associated with low eGFR level. However, faster eGFR decline was associated with global cognitive decline and incident dementia with vascular component, suggesting that this association may be mediated by vascular mechanisms.

Urinary 8-hydroxy-2-deoxyguanosine and cognitive function in Puerto Rican adults.

DNA oxidative stress has been suggested as an important pathogenic mechanism in cognitive impairment and dementia. With baseline data collected from 2004 to 2008, the authors examined whether urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), a biomarker of global DNA oxidation, was associated with cognitive function in a sample of 1,003 Puerto Rican adults, aged 45-75 years, living in Boston, Massachusetts, and the surrounding area. Cognitive function was measured by using a battery of 7 tests: the Mini-Mental State Examination, word list learning, digit span, clock drawing and figure copying, Stroop, and verbal fluency tests. The primary outcome was a global cognitive score, averaging standardized scores across all cognitive tests. A higher 8-OHdG concentration was significantly associated with lower global cognitive scores, after adjustment for age, education, status of the gene for apolipoprotein E (APOE), and other covariates (P(trend) = 0.01). The difference in the global score, comparing participants in the 2 extreme 8-OHdG quartiles, was -0.11 (95% confidence interval: -0.20, -0.02), which was equivalent to accelerating cognitive aging by about 4 years, as observed in this population. Prospective studies are needed to elucidate whether elevated urinary 8-OHdG concentrations can predict the rate of cognitive decline and incident dementia.

Improved cognitive-cerebral function in older adults with chromium supplementation.

Insulin resistance is implicated in the pathophysiological changes associated with Alzheimer's disease, and pharmaceutical treatments that overcome insulin resistance improve memory function in subjects with mild cognitive impairment (MCI) and early Alzheimer's disease. Chromium (Cr) supplementation improves glucose disposal in patients with insulin resistance and diabetes. We sought to assess whether supplementation with Cr might improve memory and neural function in older adults with cognitive decline. In a placebo-controlled, double-blind trial, we randomly assigned 26 older adults to receive either chromium picolinate (CrPic) or placebo for 12 weeks. Memory and depression were assessed prior to treatment initiation and during the final week of treatment. We also performed functional magnetic resonance imaging (fMRI) scans on a subset of subjects. Although learning rate and retention were not enhanced by CrPic supplementation, we observed reduced semantic interference on learning, recall, and recognition memory tasks. In addition, fMRI indicated comparatively increased activation for the CrPic subjects in right thalamic, right temporal, right posterior parietal, and bifrontal regions. These findings suggest that supplementation with CrPic can enhance cognitive inhibitory control and cerebral function in older adults at risk for neurodegeneration.

Systemic tocopherols and F2-isoprostanes and the risk of Alzheimer's disease and dementia: a prospective population-based study.

Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum alpha- and gamma-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679). Cox regression analyses were used to examine associations between serum alpha-, gamma-tocopherol and urinary F2-isoprostane levels and AD, any type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum alpha- and gamma-tocopherol or urinary F2-isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum alpha- and gamma-tocopherol and urinary F2-isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia.

Biomarkers for Alzheimer disease in cerebrospinal fluid, urine, and blood.

Alzheimer disease is the most common cause of dementia, yet its clinical diagnosis remains uncertain until an eventual postmortem histopathology examination. Currently, therapy for patients with Alzheimer disease only treats the symptoms; however, it is anticipated that new disease-modifying drugs will soon become available.Diagnostic tools for detecting Alzheimer disease at an incipient stage that can reliably differentiate the disease from other forms of dementia are of key importance for optimal treatment. Biomarkers have the potential to aid in a correct diagnosis, and great progress has been made in the discovery and development of potentially useful biomarkers in recent years. This includes single protein biomarkers in the cerebrospinal fluid, as well as multi-component biomarkers, and biomarkers based on gene expression. Novel biomarkers that use blood and urine, the more easily available clinical samples, are also being discovered and developed. The plethora of potential biomarkers currently being investigated may soon provide biomarkers that fulfill different functions, not only for diagnostic purposes but also for drug development and to follow disease progression.

Progressive dementia and hypersomnolence with dream-enacting behavior: oneiric dementia.

BACKGROUND: Sleep disorders are associated with several types of degenerative dementias, including Alzheimer and prion diseases. Animal models have demonstrated abolition of rapid eye movement atonia, resulting in dream-enacting complex movements termed oneiric behavior, and patients with fatal familial insomnia may have vivid dreams that intrude on wakefulness. OBJECTIVE: To describe a new form of progressive dementia with hypersomnia and oneiric behavior. METHODS: Neuropsychological and polysomnographic studies of a middle-aged woman with a progressive dementia, excessive daytime sleepiness, and a vertical gaze palsy. RESULTS: Neuropsychological testing revealed decreased verbal fluency, impaired attention and working memory, amnesia, poor recall, and bradyphrenia with hypersomnia. Polysomnography revealed a rapid eye movement behavioral disorder with complete absence of slow wave sleep. Prion protein analysis did not reveal the mutation associated with fatal familial insomnia, and other diagnostic test findings were unrevealing. CONCLUSION: Our patient had a previously unreported syndrome of progressive dementia associated with rapid eye movement behavioral disorder and the absence of slow wave sleep.

Urinary incontinence in senile dementia of the Alzheimer type (SDAT).

Twenty patients (1 male and 19 females) with senile dementia of the Alzheimer type were studied using cystometry in combination with sphincter electromyography, brain computed tomography (CT) and evaluating the activities of daily life (ADL), with special reference to urinary incontinence. Seven of the patients were continent and the remainder were incontinent. Cystometry revealed uninhibited detrusor contraction in 8 out of the 13 incontinent patients, while no uninhibited contraction was found in 7 continent patients. There was a significant correlation between uninhibited detrusor contraction and urinary incontinence (p < 0.05). Brain CT showed that the degree of brain atrophy was more severe in those with uninhibited contraction than those without (p < 0.05). There was no clear relationship between sphincter coordination and the occurrence of incontinence. The ADL score tended to be lower in incontinent patients, although no significant difference was apparent (0.05 < p < 0.1). Uninhibited detrusor contraction and poor ADL functioning caused by brain atrophy are thought to be major causes of urinary incontinence in patients with senile dementia of Alzheimer type.