Thiamine Deficiency Treatment Research Articles

Validated, unified theory of Alzheimer Disease illuminates two essential research questions

AbstractBackgroundA 2001 unified theory of thiamine deficiency (TD) in Alzheimer Disease (AD) (1‐p.85) was validated in 2015 (2), and published in 2017 (3). Update?MethodScientific literature review on topic of thiamine and/or AD. PUBMED, elibrary.wiley.com, mspace.lib.umanitoba.caResult1. Thiamine supplementation can potentially correct key AD abnormalities: the cholinergic deficit (1‐p.64, 4), B‐Amyloid (1‐p. 77, 3), tau (5), neuroinflammation (4, 5,6, 7) and memory (1‐p59).2. Limited oral thiamine supplementation trials in AD have had mixed results (1‐p49, 6).ConclusionEssential research questions:a. What causes TD in AD? (altered thiamine requirements, excretion, absorption, transport, metabolism, or diet and other factors*?) (1)b. What is the optimal treatment of TD in AD? (control for medications*, medical conditions* and dietary components affecting thiamine intake and utilization* (1‐p. 52, 1‐p.53,9). Consider advantages of intramuscular injections vs. oral treatments (8), need for other nutrients (1‐p.52), proven thiamine treatments in TD diseases.

Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital

Acute thiamine deficiency can occur in patients with or without history of alcohol abuse and can lead to life-threatening complications. Clinical diagnosis is challenging, often resulting in delayed recognition and treatment. Patients may present with heterogenous symptoms, more diverse than the historical neurological description. Cerebral MRI can contribute to the diagnosis in patients with neurological signs but it is not always feasible in emergency settings. Prompt parenteral supplementation is required to obtain the improvement of symptoms and avoid chronic complications. To describe the clinical presentation of reported cases of thiamine deficiency, assess prescription and results of cerebral imaging, review treatments that had been prescribed in accordance or not with available guidelines, and study the short-term outcome of these patients. This is a monocentric retrospective analysis of all reported cases of thiamine deficiency in a French tertiary hospital between January 1st 2008 and December 31st 2018. Fifty-six cases were identified during the study period. Forty-five (80%) patients had a history of alcohol abuse. Most patients were diagnosed based on neurological symptoms but non-specific and digestive symptoms were frequent. Thirty-four percent of patients fulfilled clinical criteria for malnutrition. A brain MRI was performed in 54% of patients and was abnormal in 63% of these cases. Eighty-five percent of patients were treated by parenteral thiamine administration and the supplementation was continued orally in 55% of them. The majority of patients initially received 1000mg daily of IV thiamine but the dose and duration of thiamine supplementation were variable. At the time of discharge, partial or complete improvement of symptoms was noted in 59% of patients. This study highlights the clinical and radiological heterogeneity of thiamine deficiency. These observations should encourage starting thiamine supplementation early in patients with risk factors or suggestive symptoms even in non-alcoholic patients, and underline the importance of early nutritional support.

Thiamine deficiency after sleeve gastrectomy

The prevalence of morbid obesity has risen to global epidemic proportions. Bariatric surgery has been proven to be a safe and effective treatment for obesity with weight reduction, resolution of obesity-related co-morbidities, improved quality of life and an increased life expectancy. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure worldwide. Obesity is associated with micronutrient deficiencies that results in the high prevalence of deficient vitamins status prior to bariatric surgery. After bariatric surgery, these micronutrient and vitamins deficiencies increase or occur de novo, and they may be threatening when left unattended. This presented clinical case demonstrates the clinical features of thiamine deficiency as well as the principles of laboratory and instrumental diagnostics. Electromyo­graphy is an informative method for diagnostic of muscle weakness. The lower serum thiamine level, neurological symptoms and electromyography results are the most important for the diagnosis of thiamine deficiency. Pathogenetic treatment can improve the patient’s condition in a short period of time. Although the SG is a purely restrictive procedure with no malabsorptive component, microelement or vitamin deficiency can occur in patients after procedure. The presented clinical case demonstrates the importance of timely thorough diagnosis and correct treatment of thiamine deficiency in patients after SG. Thus, patients after the LRS in deficiency of vitamin B1 may cause the development of neurological comp­lica­tions of varying severity, in particular dysmetabolic polyneuropathy. This condition is reversed and administration of an adequate and timely substitution therapy in patients with thiamine insufficiency allows be avoided the development of fatal complications.

Screening and treatment of thiamine deficiency in a sample of multidisciplinary bariatric surgery clinical teams.

Screening and treatment of thiamine deficiency in a sample of multidisciplinary bariatric surgery clinical teams.

Thiamine Deficiency Causes Long-Lasting Neurobehavioral Deficits in Mice.

Thiamine deficiency (TD) has detrimental effects on brain health and neurobehavioral development, and it is associated with many aging-related neurological disorders. To facilitate TD-related neuropsychological studies, we generated a TD mouse model by feeding a thiamine-deficient diet for 30 days, followed by re-feeding the control diet for either one week or 16 weeks as recovery treatment. We then performed neurobehavioral tests in these two cohorts: cohort of one week post TD treatment (1 wk-PTDT) and 16 weeks post TD treatment (16 wks-PTDT). The TD mice showed no significant difference from control in any tests in the 1 wk-PTDT cohort at the age of 13–14 weeks. The tests for the 16 wks-PTDT cohort at the age of 28–29 weeks, however, demonstrated anxiety and reduced locomotion in TD animals in open field and elevated plus maze. In comparison, rotor rod and water maze revealed no differences between TD and control mice. The current findings of the differential effects of the same TD treatment on locomotion and anxiety at different ages may reflect the progressive and moderate change of TD-induced neurobehavioral effects. The study suggests that, even though the immediate neurobehavioral impact of TD is modest or negligible at a young age, the impact could develop and become severe during the aging process.

Thalamic Proteome Changes and Behavioral Impairments in Thiamine-deficient Rats

Thiamine deficiency (TD) has been used as an experimental model in rodents to study the molecular mechanisms of neurodegeneration and its association with behavioral changes. The aims of the present study were to investigate the spatial cognitive performance of pyrithiamine-induced thiamine deficiency (PTD) in adult male rats and disclose the thalamic proteome alterations caused by a severe TD episode. After the onset of the neurological signs, such as seizure and/or loss of righting reflex, the TD treatment was interrupted. Following 15 days of recovery, all rats were submitted to the spatial cognitive tasks in the Morris Water Maze (MWM). The results show that the PTD rats exhibited deficits during the learning process, which was reverted by repeated training. However, despite the spatial cognitive recovery, some protein changes were not reversible. The proteomic analysis, using label-free quantification, revealed deregulation of 183 thalamic proteins. Using bioinformatic tools, these proteins were categorized according to Gene Ontology functional annotation and metabolic pathways. We show that a severe TD affects proteins involved in different biological processes, such as, oxidative stress, neurotransmitter synthesis and synaptic vesicle cycle. These could explain the outcome in neurotransmitter release changes caused by TD, previously observed by our group and by other authors. These findings disclose the role of key proteins and metabolic pathways probably involved in the neurodegeneration process induced by TD. These proteins represent relevant molecular targets for future studies focusing also on the molecular basis of selective vulnerability of some brain areas to TD insult.

Mechanisms of hepatic encephalopathy and thiamine deficiency.

Hepatic encephalopathy (HE) and thiamine deficiency (TD) represent two disorders in which metabolic derangements play a major role in their pathophysiology. They also define the areas of primary focus of Dr. Roger F. Butterworth, Ph.D., D.Sc. who retired from the University of Montreal in the summer of 2013. This special issue of Metabolic Brain Disease commemorates his valuable contribution to the study of these maladies. Although HE is considered a metabolic disorder, new evidence is emerging to show that it has a molecular basis as well. Vemuganti et al reports altered cerebral profiles of microRNAs after acute liver failure (ALF) that likely contribute in a significant way to gene expression changes associated with the ensuing HE. Disrupted ammonia detoxification is considered a major precipitator of neurological dysfunction in HE, and current understanding of the contribution of ammonia in liver diseases is discussed in an article by Ott and Vilstrup, while the effects of hyperammonemia on cerebral metabolic function are focussed on in an article by Schousboe and colleagues. In addition, impaired brain energy metabolism is a serious complicating feature of liver failure, with lactate production being a major consequence of this problem. In relation to this, the role of increased lactate accumulation and its pathogenetic basis in HE is discussed by Bosoi and Rose. Also, a major and often lethal complication of ALF is brain edema, and the significance of this edema and its underlying basis in ALF-induced HE is examined by Rama Rao et al, while the usefulness of magnetic resonance imaging as a tool in both acute and chronic liver failure is considered by Chavarria and Cordoba. Minimal hepatic encephalopathy (MHE) represents the mildest of the spectrum of HE forms in which patients do not display clinical symptoms but have mild cognitive and psychomotor deficits. It is also associated with poor survival rates. Two papers examine aspects of MHE, in which cognitive impairment and the issue of cognitive variability as a contributing factor in these patients is a focus of attention in Bisiacchi et al, and in an experimental model of chronic liver failure in which focal increases in the binding of translocator (18kD) protein in brain is reported by Agusti et al. Increasingly, the phenomenon of acute-on-chronic liver failure, in which acute deterioration of liver function in patients with cirrhosis is a consequence, is being considered a distinct clinical entity. The subject is discussed in Wright et al. In addition, considerable evidence has shown that astrocyte dysfunction plays a major role in HE. Karabara and colleagues explore the potential role of GlcNAcylation in these cells, while the protective effect of inhibition of glutamine synthesis is examined in neurological diseases, including HE, by Jeitner and Cooper. Development of well-defined biomarkers and improved therapeutic targets represents an important subject regarding HE. In this regard, the paper by Cooper and Kuhara shows that α-ketoglutaramate is a good marker of HE, and the paper by Mondal and Trigun demonstrates that pannexin-1 can be a marker as well as a target for HE. Although the mechanism(s) underlying the beneficial effects of rifaximin in HE remain largely unknown, the topic is tackled using multi-modal MRI in Ahluwalia et al. In addition, the subject of microglial proliferation and its significance in alcoholics with HE is explored experimentally in Dennis et al. Dienel and Cruz address the subject of decreased proteolysis as a result of hyperammonemia due to liver failure, and the effects of thioacetamide-induced ALF on citrulline uptake is examined in a study by Zielinska et al. Finally, Roger’s interest in the pathophysiology of TD has been long and enduring. A number of papers in this special issue deal with different aspects of TD. Afadlal et al shows that astrocytes play a significant role in TD-induced encephalopathy, while Bettendorff explores the role of thiamine triphosphate in cells. In addition, since mitochondrial dysfunction is an important aspect of both TD and Alzheimer’s disease in which thiamine-dependent enzyme activity is reduced, Huang et al explores how cellular calcium stores are affected in a fibroblast cell line, an important first step towards the eventual determination of how this process comes about in the AD patient and development of protective/treatment strategies targeting this mechanism, which may also have relevance for the future treatment of TD.

Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes

Loss of astrocytic glutamate transporters is a major feature of both thiamine deficiency (TD) and Wernicke’s encephalopathy. However, the underlying basis of this process is not well understood. In the present study we have investigated the possibility of release of astrocytic soluble factors that might be involved in the regulation of the glutamate transporter GLT-1b in these cells. Treatment of naïve astrocytes with conditioned media from astrocytes exposed to TD conditions resulted in a progressive decrease in glutamate uptake over 24h. Immunoblotting and flow cytometry measurements indicated this was accompanied by a 20–40% loss of GLT-1b. Astrocytes exposed to either TD or TD conditioned media showed increased disruption of mitochondrial membrane potential compared to control cells, and treatment of astrocytes with TD resulted in an increase in the pro-inflammatory cytokine TNF-α and elevated levels of phospho-IκB fragment, indicative of increased activation of NF-κB. Inhibition of TNF-α activity with the use of a neutralizing antibody blocked the increased NF-κB activation, while inhibition of NF-κB ameliorated the decrease in GLT-1b and reversed the decrease in glutamate uptake occurring with TD treatment. Together, these findings indicate that astrocytes exposed to TD conditions show responses suggesting that soluble factors released by these cells under conditions of TD play a regulatory role in terms of glutamate transport function and mitochondrial integrity.

Thiamine deficiency increases β-secretase activity and accumulation of β-amyloid peptides

Thiamine pyrophosphate (TPP) and the activities of thiamine-dependent enzymes are reduced in Alzheimer's disease (AD) patients. In this study, we analyzed the relationship between thiamine deficiency (TD) and amyloid precursor protein (APP) processing in both cellular and animal models of TD. In SH-SY5Y neuroblastoma cells overexpressing APP, TD promoted maturation of β-site APP cleaving enzyme 1 (BACE1) and increased β-secretase activity which resulted in elevated levels of β-amyloid (Aβ) as well as β-secretase cleaved C-terminal fragment (β-CTF). An inhibitor of β-secretase efficiently reduced TD-induced up-regulation of Aβ and β-CTF. Importantly, thiamine supplementation reversed the TD-induced alterations. Furthermore, TD treatment caused a significant accumulation of reactive oxygen species (ROS); antioxidants suppressed ROS production and maturation of BACE1, as well as TD-induced Aβ accumulation. On the other hand, exogenous Aβ(1-40) enhanced TD-induced production of ROS. A study on mice indicated that TD also caused Aβ accumulation in the brain, which was reversed by thiamine supplementation. Taken together, our study suggests that TD could enhance Aβ generation by promoting β-secretase activity, and the accumulation of Aβ subsequently exacerbated TD-induced oxidative stress.

Cholinergic parameters and the retrieval of learned and re-learned spatial information: A study using a model of Wernicke–Korsakoff Syndrome

This is a factorial (2 × 2 × 2) spatial memory and cholinergic parameters study in which the factors are chronic ethanol, thiamine deficiency and naivety in Morris water maze task. Both learning and retention of the spatial version of the water maze were assessed. To assess retrograde retention of spatial information, half of the rats were pre-trained on the maze before the treatment manipulations of pyrithiamine (PT)-induced thiamine deficiency and post-tested after treatment (pre-trained group). The other half of the animals was only trained after treatment to assess anterograde amnesia (post-trained group). Thiamine deficiency, associated to chronic ethanol treatment, had a significant deleterious effect on spatial memory performance of post-trained animals. The biochemical data revealed that chronic ethanol treatment reduced acetylcholinesterase (AChE) activity in the hippocampus while leaving the neocortex unchanged, whereas thiamine deficiency reduced both cortical and hippocampal AChE activity. Regarding basal and stimulated cortical acetylcholine (ACh) release, both chronic ethanol and thiamine deficiency treatments had significant main effects. Significant correlations were found between both cortical and hippocampal AChE activity and behaviour parameters for pre-trained but not for post-trained animals. Also for ACh release, the correlation found was significant only for pre-trained animals. These biochemical parameters were decreased by thiamine deficiency and chronic ethanol treatment, both in pre-trained and post-trained animals. But the correlation with the behavioural parameters was observed only for pre-trained animals, that is, those that were retrained and assessed for retrograde retention.

Primary cultures of rat astrocytes respond to thiamine deficiency-induced swelling by downregulating aquaporin-4 levels

Imaging studies indicate that cerebral edema is an important consequence of Wernicke’s encephalopathy (WE), a disorder caused by thiamine deficiency (TD). We have investigated this problem using a recently developed in vitro astrocyte model of TD. Measurement of cell volume using the 3- O-methylglucose uptake method revealed a dose-dependent swelling of astrocytes during exposure to TD conditions. Time course studies indicated a progressive volume increase up to a maximum of 93% above controls after 4 days of treatment. This swelling then partially resolved, and remained stable for up to 10 days following commencement of TD treatment. Measurement of aquaporin-4 (AQP-4) levels showed a 44% loss after 10 days and a temporal profile consistent with an important role for this water channel protein in astrocyte cell volume changes during TD. Our findings of astrocyte swelling in TD are consistent with previous reports of focal brain edema in cases of WE, and indicate that AQP-4 may be an important target for ameliorating some of the clinical problems associated with this disorder.