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AbstractThe kinematic discretisation technique of upper bound limit analysis is adopted in this study to evaluate the limit load of a strip footing located on the soils reinforced with different geosynthetic layers. The reinforcement is assumed to withstand the tension but not bending moment. The failure model of the reinforced foundation soil is generated using the discretisation method, a ‘point by point’ technique. Two failure modes of the reinforcement, the tensile rupture and sliding, are considered in the analysis. This article proposed the formulas for the first time to evaluate the effect of soil friction angle φ on the ultimate bearing capacity and on the failure mechanism of foundation. The calculation results are given considering different reinforcement layers, which describe the impact of different reinforcement depth and length on the ultimate bearing capacity. The optimum positions of different reinforcement layers and the optimum reinforcement length are obtained. The bearing capacity ratios are also presented in figures combing impact of reinforcement depths, soil cohesion and friction angle. The present method was verified by the results reported in literature. The present method can provide a reference for the footing design on the reinforced soils. [ABSTRACT FROM AUTHOR]

Based on the nonlinear failure criterion and modified tangential technique, the upper bound solutions of the critical supporting pressure on the deep tunnel face were obtained under pore water pressure conditions. The influence of parameters on the critical supporting pressure and collapse range was investigated according to the unlimited block failure mechanism. It was found that the upper bound solutions of the critical supporting pressure increase with the growth of the nonlinear coefficient and pore water pressure coefficient. The collapse range of the tunnel face scales out with the increase in the nonlinear coefficient and shrinks with an increasing pore water pressure coefficient. Moreover, with the increase in the nonlinear coefficient, the impact strength on critical supporting pressure and collapse range declines gradually. According to the calculated results, both the pore water pressure and nonlinear criterion factors have negative impacts on the stability of the tunnel face. Thus, more attention should be paid to these parameters to ensure face stability in deep tunnel construction. [ABSTRACT FROM AUTHOR]

Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains. Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) across ten brain regions. Case–control differences were determined by nonparametric Mann–Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions. Plain Language Summary: Decreases in a molecule called pantothenic acid (also known as vitamin B5) have been observed in several areas of the brain in multiple dementia disease, including Alzheimer's disease, Parkinson's disease dementia, and Huntington's disease. However, it is unknown whether such changes also occur in another dementia disease, dementia with Lewy bodies, which shows many of the same symptoms and molecular changes as these conditions. As such, this study was performed in order to determine if and where changes in pantothenic acid occur throughout the dementia with Lewy bodies brain. Using a methodology called liquid chromatography–mass spectrometry, which is able to measure pantothenic acid levels in a highly precise manner in brain tissues, we found that several regions of the dementia with Lewy bodies brain show decreases in pantothenic acid, including some involved in movement such as the substantia nigra and motor cortex, as well as regions associated with cognition and memory such as the hippocampus—looking most similar to the pattern of changes already seen in Alzheimer's disease. It is possible that these changes contribute to the progression of dementia with Lewy bodies; however, further studies need to be performed to determine at what point these changes happen during the disease and how they may contribute to the development of symptoms. [ABSTRACT FROM AUTHOR]

A three‐dimensional (3D) collapse mechanism was employed in this work to investigate the roof stability of deep‐buried cylindrical tunnels in soil considering strength nonlinearity. Based on the kinematic approach of limit analysis, three tunnel roof stability measures, namely, the stability number, the required support pressure, and the factor of safety solutions were derived to provide quantitative indicators for evaluating tunnel roof stability. Optimal upper bound solutions for these measures were obtained through optimization. Subsequently, the effects of soil strength nonlinearity and 3D geometry characteristics on roof stability and the profiles of collapsing blocks were investigated: The increase in the nonlinear coefficient m and the tensile strength σt, as well as the decrease in the initial cohesion c0, will lead to a deterioration in the stability of the tunnel roof, and also result in a larger range of collapse blocks of the tunnel roof. A 3D stability analysis of the tunnel roof can provide more reasonable stability estimates than a 2D stability analysis. When the length‐to‐radius ratio L/R → ∞, the 2D solution results. [ABSTRACT FROM AUTHOR]

The active earth pressure of earth-retaining structures (ERSs) is highly dependent on rainfall infiltration. In prior studies, ERS stability was primarily explored based on backfills under unsaturated steady flows or those that were saturated or dry while neglecting the time-dependent properties of the rainfall infiltration procedure. Accordingly, this study assessed the stability of a three-dimensional (3D) unsaturated ERS under diverse modes of rainfall infiltration by exploiting the upper bound theorem of limit analysis. A modified Green–Ampt model was adopted to consider the development of the wetting front; thereafter, an energy equilibrium equation was built to analytically derive the active earth pressure. The effects of the wall friction angle, ERS 3D geometrical characteristics, rainfall infiltration intensity and duration, and rainfall patterns on the active earth pressure coefficient were investigated. According to the results, the wall friction angle and 3D geometrical characteristics lead to a smaller active earth pressure and a superior stability state. The matric suction is a direct determinant of the active earth pressure and stability of the ERS; these exert major effects on the infiltration rate of rainfall into the soil. Furthermore, the rainfall pattern and intensity also have significant impacts on the active earth pressure and the development of the wetting front. [ABSTRACT FROM AUTHOR]

The present study performs a stability analysis of a three-dimensional (3D) rock slope in disturbed rock masses following the Generalized Hoek–Brown (GHB) failure criterion. The factor of safety (FoS) of the slope is derived and the optimal solution is captured combining the limit analysis method and the strength reduction technique. It is indicated by the parametric analysis that the 3D geometric characteristics have a significant impact on slope stability such that FoS decreases sharply with the increase in the width-to-height ratio B / H within 0 < B / H ≤ 2.0 and thereafter reaches a constant value asymptotically. The FoS decreases more than 60% linearly when the disturbance factor D increases from 0 to 1.0. Stability charts and slope angle weight factor fβ_3D for 3D slopes are proposed to provide a convenient and straightforward approach to obtain the FoS solutions of 3D slopes. A case study was carried out to apply the stability charts on practical engineering cases, which showed that slope stability under two-dimensional (2D) plane strain will lead to conservative results, and a 3D stability analysis of slope is more appropriate, especially for a slope with a limited width. [ABSTRACT FROM AUTHOR]

Rainfall infiltration can alter the pore-water pressure and decrease matric suction, which can lead to slope instability and landslides. Most of the previous numerical studies conducted on rain infiltration have assumed a two-dimensional (2D) failure mechanism, which neglects the three-dimensional (3D) characteristics of slopes. An analytical assessment framework was developed using the upper-bound theorem of limit analysis to determine the factor of safety and failure pattern in the case of a 3D vertical cut slope under diverse rainfall situations combined with the unsaturated soil mechanics. The Green–Ampt model was adopted to depict the infiltration process and the progression of the wetting front into the soil. The slope factor of safety was determined using the energy balance equation by adopting the strength reduction approach. The validity of the framework was verified using the numerical simulation method. The effects of duration, intensity, and patterns of rainfall and the 3D traits of slope on the slope failure pattern and stability were determined. A set of design charts was included for the preliminary design. The present study quantitatively determines the stability of slopes susceptible to rainfall infiltration. [ABSTRACT FROM AUTHOR]

Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal post-mortem tissue from cases with VaD (n = 10) and age-/sex-matched controls (n = 10). We also applied principal component analysis to compare the metallomic pattern of VaD in the hippocampus with our previous hippocampal metal datasets for Alzheimer's disease, Huntington's disease, Parkinson's disease, and type-2 diabetes, which had been measured using the same methodology. We found substantive novel evidence for elevated hippocampal Na levels and Na/K ratios in both wet- and dry-weight analyses, whereas decreased K levels were present only in wet tissue. Multivariate analysis revealed no distinguishable hippocampal differences in metal-evoked patterns between these dementia-causing diseases in this study. Contrasting levels of Na and K in hippocampal VaD tissue may suggest dysfunction of the Na+/K+-exchanging ATPase (EC 7.2.2.13), possibly stemming from deficient metabolic energy (ATP) generation. These findings therefore highlight the potential diagnostic importance of cerebral sodium measurement in VaD patients. [ABSTRACT FROM AUTHOR]

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer's disease (AD) and Huntington's disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson's disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure and function to seek new disease-related mechanisms that might be targeted by novel disease-modifying interventions. During hypothesis-generating proteomic investigations in a case-control study of sAD, we observed widespread elevations of haptoglobin and haemopexin in all six brain-regions studied, which together represent much of the brain. Measured perturbations were significant, with the posterior probability of upregulation generally >95% and haptoglobin doubling in expression levels on average across deep brain structures (hippocampus, entorhinal cortex and cingulate gyrus) as well as sensory and motor cortices, and cerebellum. Haptoglobin and haemopexin are often regarded as circulating proteins whose main functions are to bind, respectively, the strongly pro-inflammatory extracellular haemoglobin and haeme molecules that form following haemolysis, thereby promoting their clearance and suppressing damage they might otherwise cause, for example, acute kidney injury. To our knowledge, elevations in neither cerebral haptoglobin nor haemopexin have previously been linked to the pathogenesis of sAD. Post-mortem examination of these cases showed no signs of macroscopic cerebral haemorrhage. These findings demonstrate pervasive cerebral elevation of haptoglobin and haemopexin, consistent with low-level intracerebral leakage of haemoglobin and consequent haeme formation throughout sAD brain. They point to a widespread underlying microvasculopathy that facilitates erythrocyte leakage, thereby triggering elevated tissue-free haemoglobin and driving the measured elevations in haptoglobin and haemopexin. • Widespread elevations of cerebral haptoglobin and haemopexin in sAD. • Elevated fibrinogen suggests widespread leakiness of the blood-brain barrier in sAD. • No evidence of post-mortem cerebral bleeding in all cases. • Potential occurrence of a glucose-driven microvasculopathy in sAD. [ABSTRACT FROM AUTHOR]

Several studies of Parkinson's disease (PD) have reported dysregulation of cerebral metals, particularly decreases in copper and increases in iron in substantia nigra (SN). However, few studies have investigated regions outside the SN, fewer have measured levels of multiple metals across different regions within the same brains, and there are no currently-available reports of metal levels in Parkinson's disease dementia (PDD). This study aimed to compare concentrations of nine essential metals across nine different brain regions in cases of PDD and controls. Investigated were: primary motor cortex (MCX); cingulate gyrus (CG); primary visual cortex (PVC); hippocampus (HP); cerebellar cortex (CB); SN; locus coeruleus (LC); medulla oblongata (MED); and middle temporal gyrus (MTG), thus covering regions with severe, moderate, or low levels of neuronal loss in PDD. Levels of eight essential metals and selenium were determined using an analytical methodology involving the use of inductively-coupled plasma mass spectrometry (ICP-MS), and compared between cases and controls, to better understand the extent and severity of metal perturbations. Findings were also compared with those from our previous study of sporadic Alzheimer's disease dementia (ADD), which employed equivalent methods, to identify differences and similarities between these conditions. Widespread copper decreases occurred in PDD in seven of nine regions (exceptions being LC and CB). Four PDD-affected regions showed similar decreases in ADD: CG, HP, MTG, and MCX. Decreases in potassium and manganese were present in HP, MTG and MCX; decreased manganese was also found in SN and MED. Decreased selenium and magnesium were present in MCX, and decreased zinc in HP. There was no evidence for increased iron in SN or any other region. These results identify alterations in levels of several metals across multiple regions of PDD brain, the commonest being widespread decreases in copper that closely resemble those in ADD, pointing to similar disease mechanisms in both dementias. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and dementia, and there are no available treatments with proven disease-modifying actions. It is therefore appropriate to study hitherto-unknown aspects of brain structure/function in AD to seek alternative disease-related mechanisms that might be targeted by new therapeutic interventions with disease-modifying actions. During hypothesis-generating metabolomic studies of brain, we identified apparent differences in levels of vitamin B5 between AD cases and controls. We therefore developed a method based on gas chromatography-mass spectrometry by which we quantitated vitamin B5 concentrations in seven brain regions from nine AD cases and nine controls. We found that widespread, severe cerebral deficiency of vitamin B5 occurs in AD. This deficiency was worse in those regions known to undergo severe damage, including the hippocampus, entorhinal cortex, and middle temporal gyrus. Vitamin B5 is the obligate precursor of CoA/acetyl-CoA (acetyl-coenzyme A), which plays myriad key roles in the metabolism of all organs, including the brain. In brain, acetyl-CoA is the obligate precursor of the neurotransmitter acetylcholine, and the complex fatty-acyl groups that mediate the essential insulator role of myelin, both processes being defective in AD; moreover, the large cerebral vitamin B5 concentrations co-localize almost entirely to white matter. Vitamin B5 is well tolerated when administered orally to humans and other mammals. We conclude that cerebral vitamin B5 deficiency may well cause neurodegeneration and dementia in AD, which might be preventable or even reversible in its early stages, by treatment with suitable oral doses of vitamin B5. • We quantitated vitamin B5 in 7 brain regions from 9 cases of AD and 9 matched controls. • We found that widespread, severe cerebral deficiency of vitamin B5 occurs in AD. • Vitamin B5 deficiency particularly affects regions known to be severely damaged in AD. • Cerebral vitamin B5 deficiency could cause neurodegeneration and dementia in AD. • AD-evoked dementia might be preventable/treatable with suitable oral doses of vitamin B5. [ABSTRACT FROM AUTHOR]

Nitrogen is an essential macronutrient for plants and the common limiting factor for crop productivity worldwide. An effective approach to combat N deficiency and overuse is to understand the mechanism of low-nitrogen tolerance in plants and develop low-nitrogen-tolerant crop cultivars. Wild soybean has a high tolerance to poor environmental conditions, but, until now, no study has illustrated the mechanism of low-nitrogen tolerance at a metabolomic level. In this study, the photosynthetic characteristics and metabolomics of wild and cultivated soybean seedlings were analyzed, and the mechanism of wild soybean’s low-nitrogen tolerance was explained using a sand culture experiment. Wild soybean was less affected by low-nitrogen stress than cultivated soybean as assessed by plant growth parameters and photosynthesis. The root length of wild soybean increased, and a high root-shoot ratio was maintained under low-nitrogen stress. Carotenoids accumulated, which contributed to its higher low-nitrogen tolerance. A total of 48 and 60 differentially accumulated metabolites were identified in leaves and roots, respectively, between the low-nitrogen stress and control groups. The ability of wild soybean to tolerate low nitrogen also resulted from its capability to enhance the TCA cycle, synthesize key amino acids, accumulate metabolites, such as soluble sugars and organic acids, and synthesize favorable secondary metabolites under low-nitrogen stress. The current results reveal the mechanism underlying wild soybean’s high low-nitrogen tolerance and provide the methodology and theoretical basis for utilizing wild soybean, improving cultivated soybean, and studying the low-nitrogen tolerance of other plants. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism. [ABSTRACT FROM AUTHOR]

Pantothenic acid (vitamin B5) is an essential trace nutrient required for the synthesis of coenzyme A (CoA). It has previously been shown that pantothenic acid is significantly decreased in multiple brain regions in both Alzheimer's disease (ADD) and Huntington's disease (HD). The current investigation aimed to determine whether similar changes are also present in cases of Parkinson's disease dementia (PDD), another age-related neurodegenerative condition, and whether such perturbations might occur in similar regions in these apparently different diseases. Brain tissue was obtained from nine confirmed cases of PDD and nine controls with a post-mortem delay of 26 h or less. Tissues were acquired from nine regions that show high, moderate, or low levels of neurodegeneration in PDD: the cerebellum, motor cortex, primary visual cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons. A targeted ultra–high performance liquid chromatography—tandem mass spectrometry (UHPLC-MS/MS) approach was used to quantify pantothenic acid in these tissues. Pantothenic acid was significantly decreased in the cerebellum (p = 0.008), substantia nigra (p = 0.02), and medulla (p = 0.008) of PDD cases. These findings mirror the significant decreases in the cerebellum of both ADD and HD cases, as well as the substantia nigra, putamen, middle frontal gyrus, and entorhinal cortex of HD cases, and motor cortex, primary visual cortex, hippocampus, middle temporal gyrus, cingulate gyrus, and entorhinal cortex of ADD cases. Taken together, these observations indicate a common but regionally selective disruption of pantothenic acid levels across PDD, ADD, and HD. [ABSTRACT FROM AUTHOR]

The use of post-mortem human tissue is indispensable in studies investigating alterations in metabolite levels in neurodegenerative conditions such as Alzheimer's disease (AD). However, variability between samples may have unknown effects on metabolite concentrations. The aim of this study was to characterize the impact of such variables. Cingulate gyrus was obtained from AD cases and controls, from three brain banks. Gas chromatography-mass spectrometry (GC-MS) was used to measure and compare the levels of 66 identifiable metabolites in these tissues to determine effects of tissue-collection variables. The effect of PMD was further investigated by analysis of rat brain cortex and cerebellum collected following post-mortem delays (PMDs) of zero to 72 h. Metabolite levels between cases and controls were not replicable across cohorts with variable age- and gender-matching, PMD, and control Braak staging. Analysis of rat tissues found significant effects of PMD on 31 of 63 identified metabolites over periods up to 72 h. PMD must be kept under 24 h for metabolomics analyses on brain tissues to yield replicable results. Tissues should also be well age- and gender-matched, and Braak stage in controls should be kept to a minimum in order to minimize the impact of these variables in influencing metabolite variability. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5. [ABSTRACT FROM AUTHOR]