I like to keep challenging the items in my stack. HDT is in my stack. I believe in HDT. But why? So far I trust HDT because of the results from Dr Constantini and the testimonials. Time to look for some science:
Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults - 2019 - ncbi.nlm.nih.gov/pmc/articl...
1) It has sulfur: The essential nutrient thiamine (vitamin B1) is a water-soluble, sulfur-containing vitamin belonging to the vitamin B complex family.
2) And there is this: Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production.
3) Up to 90% of the total thiamine in the body remains in its diphosphate, metabolically active form (TPP), whereas the rest is found as TMP and TTP (45). TPP is a cofactor of several thiamine-dependent enzymes involved in carbohydrate and fatty acid metabolism, namely, cytosolic transketolase (TKT), peroxisomal 2-hydroxyacyl-CoA lyase 1, and three mitochondrial enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase complexes.
4) In the cytosol, TPP acts as a cofactor for TKT, a key enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP). This metabolic pathway generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribose 5-phosphate (R5P) (47). NADPH is a key reducing agent in biosynthetic reactions and is a co-substrate of biosynthetic enzymes (fatty acid synthesis) and antioxidant enzymes such as the glutathione peroxidase–reductase system and thioredoxin peroxidases, among others.
5) Mitochondria: Most (∼90%) of the cytosolic TPP is transported into mitochondria via the mitochondrial thiamine pyrophosphate transporter [MTPPT, product of the SLC25A19 gene (56)]. This transporter mediates the exchange of cytosolic TPP for the mitochondrial TMP; once in the cytosol, TMP is metabolized and converted back to TPP (56). In mitochondria, TPP is a critical cofactor for three enzymes, namely, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase (PDH, αKGDH, and BCKDH, respectively).
Then there is Dr Constantini's work: An open-label pilot study with high-dose thiamine in Parkinson's disease - 2016 - ncbi.nlm.nih.gov/pmc/articl...
1) TD (Thiamine Deficiency) pathophysiology involves several events and results in focal neuronal cell death. Such events, e.g., the reduced activity of alpha-keto-glutarate dehydrogenase, the impaired oxidative metabolism, the increased oxidative stress, and the selective neuronal loss in specific brain regions, represent also some pathological mechanisms involved in the neurodegenerative diseases. TD reduces the activity of the thiamine-dependent enzymes with regional selectivity, being different cerebral areas affected with different severity (Butterworth, 2003). TD could then be an useful model in neurodegeneration (Jhala and Hazell, 2011). New studies suggest that thiamine has also non-coenzymatic roles, potentially relevant in neuroprotection (Mkrtchyan, 2015).
2) Several studies demonstrated a link between PD and thiamine (Lu’o’ng and Nguyên, 2011). A decreased activity of the thiamine-dependent enzymes and a selective loss of the mitochondrial complex I have been reported in the nigral neurons of patients with PD (Butterworth, 2003; Schapira, 2014). In the cerebrospinal fluid of patients with PD, free thiamine levels are lower than controls (Jiménez-Jiménez et al., 1999).
3) In the brain of patients with PD, a reduction in glucose metabolism and an increase of oxidative stress have been reported; in fact, the thiamine-dependent processes are critical in the glucose metabolism, and recent studies implicate thiamine in the oxidative stress, the protein processing, the peroxisomal function, and the gene expression (Brandis et al., 2006; Jhala and Hazell, 2011).
4) Moreover, an interesting study about an alpha-synuclein fission yeast model found that thiamine lowers the alpha-synuclein expression in a dose-dependent manner and that A53T mutated alpha-synuclein aggregates at lower concentrations than wild-type alpha-synuclein: these data suggest that increasing intracellular thiamine could reduce the alpha-synuclein concentration and then the alpha-synuclein aggregation (Brandis et al., 2006).
5) We suppose that the improvement of the energetic metabolism of the survivors neurons in the substantia nigra, due to the high doses of thiamine, could lead to an increase of synthesis and release of the endogenous dopamine, to an increase of activity of the thiamine-dependent enzymes, or to a better utilization of the exogenous levodopa (Jiménez-Jiménez et al., 1999; Lu’o’ng and Nguyên, 2012; Costantini et al. 2015). We suggest that the abnormalities in the thiamine-dependent processes could be overcome by a diffusion-mediated transport at supranormal thiamine concentrations.
6) Considering that there is no correlation between the positive effects of thiamine administration and the brain levels of thiamine diphosphate or thiamine diphosphate-dependent enzymatic activities, the potential contribution of the non-coenzyme action of thiamine should not be neglected in patients with neurodegenerative diseases (Mkrtchyan et al., 2015).
7) The high dose of thiamine may elevate not only thiamine diphosphate, but also the non-coenzyme forms, which may thus be also responsible for the therapeutic effects of thiamine.
8) The recently identified protein targets and mechanisms of the non-coenzyme action of thiamine could be important for the neuroprotection (Lu’o’ng and Nguyên, 2012; Mkrtchyan et al., 2015).
9) Based on preclinical and clinical data, the clinical efficacy of continuous treatment with high doses of thiamine in our patients with PD could indicate that PD symptomatology is the manifestation of neuronal TD. A dysfunction of thiamine-dependent metabolic pathways, either via coenzymatic or non-coenzymatic processes, could cause a selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration (Butterworth, 2003; Jhala and Hazell, 2011; Mkrtchyan et al., 2015).
Then I jumped over to an article Dr Constantini refferrenced: Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis - 2015 - nature.com/articles/srep12583
1) Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP). However, positive effects, including improved cognition, of high thiamin doses in neurodegeneration may be observed without increased ThDP or ThDP-dependent enzymes in brain.
2) Thiamin (also known as vitamin B1) is widely used in neuropharmacology. In particular, its administration causes a transient improvement in cognitive function of some patients affected by neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD).
3) In patients with neurodegenerative diseases, such as AD and fronto-temporal dementia, significantly less ThDP than in the age-matched control group was determined in post-mortem cortex samples.
3) Several features of thiamin pharmacology are worth noting. First, rather high doses of this vitamin (e.g. app. 14- and 90-fold excesses over the recommended daily dose in a Vitamin B-Komplex of Ratiopharm GmbH, Germany and Neuromultivit of Lannacher Heilmittel GmbH, Austria, respectively) can be employed in medical practice, as they are not known to have adverse effects. Second, apart from the widely accepted ThDP action as a coenzyme of central metabolism, thiamin has long been known to co-release with acetylcholine9,10,11 facilitating synaptic transmission12. Independent studies suggested the involvement of proteins of synaptosomal plasmatic membrane hydrolyzing the non-coenzyme derivative thiamin triphosphate (ThTP)13,14,15,16,17 and phosphorylating synaptic proteins with ThTP as a phosphate donor.
4) Another important aspect is that pharmacological compounds often possess heterocycles which are structurally similar to those present in thiamin and derivatives and may therefore act by targeting thiamin-dependent pathways23. In particular, drugs which reduce hyperphosphorylated tau-protein in AD mouse models24 possess structural similarity to thiamin and may therefore mimic or interfere with the pathways of the thiamin non-coenzyme action in synaptic transmission. The existence of such pathways, in addition to the known metabolic role of ThDP, could explain the absence of a robust correlation between positive effects of thiamin in patients with neurodegenerative diseases and activities of ThDP-dependent enzymes and ThDP levels in the brain of these patients.
I'm still sold. Time to boost my Thiamine from 500 mg to 750 mg!
