Thiamine Deficiency Increases Intrinsic Excitability of Mouse Cerebellar Purkinje Cells.

Thiamine deficiency is associated with cerebellar dysfunction; however, the consequences of thiamine deficiency on the electrophysiological properties of cerebellar Purkinje cells are poorly understood. Here, we evaluated these parameters in brain slices containing cerebellar vermis. Adult mice were maintained for 12-13 days on a thiamine-free diet coupled with daily injections of pyrithiamine, an inhibitor of thiamine phosphorylation. Morphological analysis revealed a 20% reduction in Purkinje cell and nuclear volume in thiamine-deficient animals compared to feeding-matched controls, with no reduction in cell count. Under whole-cell current clamp, thiamine-deficient Purkinje cells required significantly less current injection to fire an action potential. This reduction in rheobase was not due to a change in voltage threshold. Rather, thiamine-deficient neurons presented significantly higher input resistance specifically in the voltage range just below threshold, which increases their sensitivity to current at these critical membrane potentials. In addition, thiamine deficiency caused a significant decrease in the amplitude of the action potential afterhyperpolarization, broadened the action potential, and decreased the current threshold for depolarization block. When thiamine-deficient animals were allowed to recover for 1 week on a normal diet, rheobase, threshold, action potential half-width, and depolarization block threshold were no longer different from controls. We conclude that thiamine deficiency causes significant but reversible changes to the electrophysiology properties of Purkinje cells prior to pathological morphological alterations or cell loss. Thus, the data obtained in the present study indicate that increased excitability of Purkinje cells may represent a leading indicator of cerebellar dysfunction caused by lack of thiamine.

Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency.

BACKGROUND: Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. METHODS: Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. RESULTS: Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. CONCLUSIONS: Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.

The Use of Video-Head Impulse Test in Different Head Positions in Vertical Nystagmus and Ataxia Associated with Probable Thiamine Deficiency.

Upward and downward bias of eye movement signals in the semicircular canals (SCC)- and/or otolith-related central pathways have been proposed to explain the occurrence of vertical nystagmus (downbeat nystagmus [DBN] and upbeat nystagmus [UBN]) and its frequent modulation with head position. Video-head impulse test (VHIT), usually performed in upright position, is a recent development for measuring SCC function. We performed longitudinal nystagmus and VHIT assessments in different head positions in a patient with probable thiamine deficiency, in order to explore a possible relationship between the positional behavior of vertical nystagmus and SCC function. Initially, UBN in upright position changed to DBN in prone position and remained relatively unchanged in supine position. This was associated with both anterior and posterior SCC hyperactive responses in upright position, and a relative enhancement of the anterior SCC responses in prone position and the posterior SCC responses in supine position. Over 1 year, in prone position, change from UBN to DBN and the enhancement of anterior SCC responses remained, while in supine position, UBN either decreased or changed to DBN, when compared to upright position. This was associated with a relative enhancement of the anterior SCC responses in supine position, albeit inconsistently, and the presence of posterior SCC hypoactive responses in all positions, including prone. While not contradicting a primary otolithic dysfunction in the genesis of UBN change to DBN with head position, we provide evidence for positional modulation of SCC function in thiamine deficiency and a possible relationship with nystagmus positional behavior.

Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes.

Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Subclinical thiamine deficiency: What is the most appropriate method of diagnosis and treatment?

OBJECTIVES: The symptoms of thiamine deficiency vary considerably and asymptomatic cases; i.e., subclinical thiamine deficiency (SCTD), are known to exist. However, there is no information available on the treatment of SCTD. METHODS: We report a patient who underwent intravenous thiamine replacement therapy for about a month after being diagnosed with SCTD, but who developed SCTD again about three weeks after finishing the treatment. RESULTS: The patient was a 64-year-old woman who, after starting treatment for cervical cancer, complained of anxiety and underwent an initial psychiatric examination. The psychiatric diagnosis was an adjustment disorder. Based on the possibility of SCTD complications due to her decreased appetite and weight loss, her serum thiamine concentration was measured and found to be low. Therefore, thiamine was administered intravenously for 29 days. At the end of treatment, thiamine administration was discontinued as there were no apparent neuropsychiatric symptoms or problems with appetite. Twenty-three days later, there were still no problems with appetite or neuropsychiatric symptoms, but a follow-up blood sample revealed that her serum thiamine was again below the normal range. SIGNIFICANCE OF RESULTS: Currently, there is no information available regarding the diagnosis and treatment of SCTD in cancer patients. In some cases, such as this case, the deficiency recurs without any symptoms indicative of SCTD; therefore, further examination for diagnosis and treatment is necessary.

Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4.

Thiamine metabolism dysfunction syndrome-4 (THMD4) includes episodic encephalopathy, often associated with a febrile illness, causing transient neurologic dysfunction and a slowly progressive axonal polyneuropathy. Until now only two mutations (G125S and S194P) have been reported in the SLC25A19 gene as causative for this disease and a third mutation (G177A) as related to the Amish lethal microcephaly. In this work, we describe the clinical and molecular features of a patient carrying a novel mutation (c.576G>C; Q192H) on SLC25A19 gene. Functional studies on this mutation were performed explaining the pathogenetic role of c.576G>C in affecting the translational efficiency and/or stability of hMTPPT protein instead of the mRNA expression. These findings support the pathogenetic role of Q192H (c.576G>C) mutation on SLC25A19 gene. Moreover, despite in other patients the thiamine supplementation leaded to a substantial improvement of peripheral neuropathy, our patient did not show a clinical improvement.

Thiamine deficiency observed in a cancer patient's caregiver.

OBJECTIVE: Thiamine deficiency (TD) is recognized in various kinds of disease with associated loss of appetite including cancer; however, TD has not been recognized in the family caregivers of cancer patients to date. METHOD: From a series of cancer patient caregivers, we reported an aged family caregiver who developed TD while caring for the cancer patient. RESULT: The caregiver was a 90-year-old male. He had been accompanying his wife, who was diagnosed with colon cancer 4 years previously, on hospital visits as the primary caregiver, but because of psychological issues, he was recommended to visit the psycho-oncology department's "caregiver's clinic" for a consultation. Detailed examination revealed that his appetite had been only about 50% of usual from about one year before, and he had lost 12 kg in weight in one year. The diagnosis of TD was supported by his abnormally low serum thiamine level. SIGNIFICANCE OF THE RESULTS: This report demonstrates that there is a possibility that care providers could develop TD from the burdens associated with caregiving. TD should be considered whenever there is a loss of appetite lasting for more than 2 weeks, and medical staff should pay careful attention to the physical condition of care providers to prevent complications resulting from TD.

Thiamine deficiency contributes to synapse and neural circuit defects.

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Thiamine Levels in Muscle and Eggs of Adult Pacific Salmon from the Fraser River, British Columbia.

Multiple species and stocks of Pacific salmon Oncorhynchus spp. have experienced large declines in the number of returning adults over a wide region of the Pacific Northwest due to poor marine survival (low smolt-to-adult survival rates). One possible explanation for reduced survival is thiamine deficiency. Thiamine (vitamin B1 ) is an essential vitamin with an integral role in many metabolic processes, and thiamine deficiency is an important cause of salmonid mortality in the Baltic Sea and in the Laurentian Great Lakes. To assess this possibility, we (1) compared muscle thiamine content over time in a holding experiment using Fraser River (British Columbia) Sockeye Salmon O. nerka to establish whether adults that died during the holding period had lower thiamine levels than survivors, (2) measured infectious loads of multiple pathogens in held fish, and (3) measured egg thiamine content from four species of Pacific salmon collected on Fraser River spawning grounds. Chinook Salmon O. tshawytscha had the lowest egg thiamine, followed by Sockeye Salmon; however, egg thiamine concentrations were above levels known to cause overt fry mortality. Thiamine vitamers in the muscle of Fraser River adult Sockeye Salmon shifted over a 13-d holding period, with a precipitous decline in thiamine pyrophosphate (the active form of thiamine used in enzyme reactions) in surviving fish. Survivors also carried lower loads of Flavobacterium psychrophilum than fish that died during in the holding period. Although there is no evidence of thiamine deficiency in the adults studied, questions remain about possible thiamine metabolism-fish pathogen relationships that influence survival.

Thiamine Deficiency Increases Ca2+ Current and CaV1.2 L-type Ca2+ Channel Levels in Cerebellum Granular Neurons.

Thiamine (vitamin B1) is co-factor for three pivotal enzymes for glycolytic metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. Thiamine deficiency leads to neurodegeneration of several brain regions, especially the cerebellum. In addition, several neurodegenerative diseases are associated with impairments of glycolytic metabolism, including Alzheimer's disease. Therefore, understanding the link between dysfunction of the glycolytic pathway and neuronal death will be an important step to comprehend the mechanism and progression of neuronal degeneration as well as the development of new treatment for neurodegenerative states. Here, using an in vitro model to study the effects of thiamine deficiency on cerebellum granule neurons, we show an increase in Ca2+ current density and CaV1.2 expression. These results indicate a link between alterations in glycolytic metabolism and changes to Ca2+ dynamics, two factors that have been implicated in neurodegeneration.

Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations.

Thiamine is an essential vitamin that is necessary to maintain the functional integrity of cells in the brain. Its deficiency is the underlying cause of Wernicke's encephalopathy (WE), a disorder primarily associated with, but not limited to, chronic alcoholism. Thiamine deficiency leads to the development of impaired energy metabolism due to mitochondrial dysfunction in focal regions of the brain resulting in cerebral vulnerability. The consequences of this include oxidative stress, excitotoxicity, inflammatory responses, decreased neurogenesis, blood-brain barrier disruption, lactic acidosis and a reduction in astrocyte functional integrity involving a loss of glutamate transporters and other astrocyte-specific proteins which together contribute in a major way to the resulting neurodegeneration. Exactly how these factors acting in concert lead to the demise of neurons is unclear. In this review we reassess their relative importance in the light of more recent findings and discuss therapeutic possibilities that may provide hope for the future for individuals with WE.

[THIAMINE--"THE ROAD EXPERIENCE" OF THE VITAMIN AS A MANIFESTATION OF DEFICIENCY IN A WORLD OF ABUNDANCE].

Thiamine or vitamin B1 is a water soluble vitamin of the vitamin B complex. It is synthetized by bacteria, fungi and plants and is an essential component of multicellular living organisms. Humans are not able to synthetize this vitamin and have to obtain it from different foods. Thiamin has a vital role in the normal function of the human body. It functions as a coenzyme in the catabolism of carbohydrates and amino acids and has an antioxidant role. It has an essential function in a series of metabolic processes related to energy production and conversion of sugar to ATP, as a catalyst in the Krebs cycle. It takes part in the synthesis of neurotransmitters and has a main role in the central nervous system and immune system. Deficiency results in Wernicke-Korsakoff syndrome, optic neuropathy, Beri-Beri and other disorders. Vitamin B deficiency in not rare and may occur in conditions related to malnutrition, alcoholism, diabetes, congestive heart failure and others. In this review an effort has been made to demonstrate the presence of thiamine deficiency in various clinical situations frequent in modern medicine, attributed in the past to populations with "classical" inadequate feeding and starvation, or severe malnutrition. Identification of potential causes of vitamin B1 deficiency, knowledge of its metabolic properties and the clinical manifestations of its deficiency are important for the implementation of early therapeutic response required for the reduction and prevention of symptoms related to this disorder.

Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders.

Wernicke encephalopathy is an acute, reversible neuropsychiatric emergency due to thiamine deficiency. Urgent and adequate thiamine replacement is necessary to avoid death or progression to Korsakoff syndrome with largely irreversible brain damage. Wernicke Korsakoff syndrome refers to a condition where features of Wernicke encephalopathy are mixed with those of Korsakoff syndrome. Although thiamine is the cornerstone of treatment of Wernicke encephalopathy, there are no universally accepted guidelines with regard to its optimal dose, mode of administration, frequency of administration or duration of treatment. Currently, different dose recommendations are being made. We present recommendations for the assessment and treatment of Wernicke encephalopathy based on literature review and our clinical experience.

Role of astrocytes in thiamine deficiency.

Thiamine deficiency (TD) is the underlying cause of Wernicke's encephalopathy (WE), an acute neurological disorder characterized by structural damage to key periventricular structures in the brain. Increasing evidence suggests these focal histological lesions may be representative of a gliopathy in which astrocyte-related changes are a major feature of the disorder. These changes include a loss of the glutamate transporters GLT-1 and GLAST concomitant with elevated interstitial glutamate levels, lowered brain pH associated with increased lactate production, decreased levels of GFAP, reduction in the levels of glutamine synthetase, swelling, alterations in levels of aquaporin-4, and disruption of the blood-brain barrier. This review focusses on how these manifestations contribute to the pathophysiology of TD and possibly WE.

Thiamine nutritional status and depressive symptoms are inversely associated among older Chinese adults.

Thiamine has been hypothesized to play an important role in mental health; however, few studies have investigated the association between thiamine nutritional status and depression in the general population. Concentrations of free thiamine and its phosphate esters [thiamine monophosphate (TMP) and thiamine diphosphate (TDP)] in erythrocytes were measured by HPLC among 1587 Chinese men and women aged 50-70 y. The presence of depressive symptoms was defined as a Center for Epidemiological Studies Depression Scale score of ≥16. The median erythrocyte concentration (nmol/L) was 3.73 for free thiamine, 3.74 for TMP, and 169 for TDP. The overall prevalence of depressive symptoms was 11.3%. Lower concentrations of all 3 erythrocyte thiamine biomarkers were monotonically associated with a higher prevalence of depressive symptoms: the multivariable adjusted ORs comparing the lowest with the highest quartiles were 2.97 (95% CI = 1.87, 4.72; P-trend < 0.001) for free thiamine, 3.46 (95% CI = 1.99, 6.02; P-trend < 0.001) for TMP, and 1.98 (95% CI = 1.22, 3.21; P-trend = 0.002) for TDP. In conclusion, poorer thiamine nutritional status and higher odds of depressive symptoms were associated among older Chinese adults. This finding should be further investigated in prospective or interventional studies.