Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Gary E Gibson, José A Luchsinger, Rosanna Cirio, Huanlian Chen, Jessica Franchino-Elder, Joseph A Hirsch, Lucien Bettendorff, Zhengming Chen, Sarah A Flowers, Linda M Gerber, Thomas Grandville, Nicole Schupf, Hui Xu, Yaakov Stern, Christian Habeck, Barry Jordan, Pasquale Fonzetti, Gary E Gibson, José A Luchsinger, Rosanna Cirio, Huanlian Chen, Jessica Franchino-Elder, Joseph A Hirsch, Lucien Bettendorff, Zhengming Chen, Sarah A Flowers, Linda M Gerber, Thomas Grandville, Nicole Schupf, Hui Xu, Yaakov Stern, Christian Habeck, Barry Jordan, Pasquale Fonzetti

Abstract

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.

Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine.

Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome.

Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002).

Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

Keywords: Advanced glycation endproducts; Alzheimer’s disease; benfotiamine; glucose; inflammation; oxidative stress.

Figures

Fig. 1.
Fig. 1.
Summary of the treatment protocol for the one-year trial.
Fig. 2.
Fig. 2.
Changes in ADAS-Cog with benfotiamine treatment compared to controls. See Table 7 for statistical comparisons.
Fig. 3.
Fig. 3.
Benfotiamine treatment and the CDR. CDR Placebo = 34, benfotiamine = 29. On the figure *** indicates significantly different (p = 0.034) (A). When the groups are also separated by sex, large but non-significant differences occur (B). When the groups are separated by APOE4 only the non-APOE ε4 allele group differs. In the non-APOE4 group the *** indicates values significantly different (p = 0.013) (C). The APOE4 denotes at least one ε4 allele. p-values here are when there are subgroups are all obtained from subgroup analysis, not interaction from ANOVA (C).
Fig. 4.
Fig. 4.
Benfotiamine and the Buschke Selective Reminding Test (SRT).
Fig. 5.
Fig. 5.
Benfotiamine and the Neuropsychiatric Inventory (NPI). No differences were seen in the overall scores (A). However, separation of the groups by sex revealed a highly significant benefit in males but not females. *** indicates p = 0.035 (B). No significant difference was seen with APOE ε4 alleles (C).
Fig. 6.
Fig. 6.
Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL).
Fig. 7.
Fig. 7.
Blood thiamine, ThMP, and ThDP concentrations at baseline and month 12. Each dot represents a different patient. The bar represents the mean value. All values are per protocol after omitting a patient designated as placebo who was taking benfotiamine from another source.
Fig. 8.
Fig. 8.
Relation of sex and APOE ε4 genotype to thiamine, ThDP and ThMP. Values are means ± SEM. *** denotes significantly different (p <0.0001) by t-test.
Fig. 9.
Fig. 9.
Advanced glycation end products (AGE) after benfotiamine treatment. These were done as an exploratory analysis. They were measured on serum and several samples were contaminated with RBC. In the left panel, the n’s are 12 placebo and 13 benfotiamine patients. The asterisk indicates p = 0.043. In the right panel, in the APOE ε4 group the n = 6. In the non-APOE4 group n = 7. The APOE ε4 denotes at least one ε4 allele.
Fig. 10
Fig. 10
A. Pattern score as function of the 12-month treatment period. The pattern is a linear combination of the first two principal components whose pattern score is slightly but significantly higher for treatment than untreated participants at time point 12 months. B. The left panel shows the pattern score plotted against CDR status (p-level obtained from whole-model F-test.) A higher pattern score implies lower CDR status. The right panel shows loading distributions from a bootstrap test with 90% coverage intervals. We stress that these loadings sizes and signs are relative since we removed the whole-brain mean from the analysis prior to the pattern derivation. Thus, high positive loadings are found in the right mid temporal and inferior parietal cortex, implying relatively higher signal in participants with lower CDR. Bilateral cerebellum and paracentral lobule on the other hand, had relatively lower signal in participants with lower CDR. C. Stratification of the pattern score by APOE status reveals that APOE4 negative patients show the greatest response. APOE ε4 = 0 patients show a treatment effect (left panel), APOE ε4 = 1 do not (right panel).
Fig. 10
Fig. 10
A. Pattern score as function of the 12-month treatment period. The pattern is a linear combination of the first two principal components whose pattern score is slightly but significantly higher for treatment than untreated participants at time point 12 months. B. The left panel shows the pattern score plotted against CDR status (p-level obtained from whole-model F-test.) A higher pattern score implies lower CDR status. The right panel shows loading distributions from a bootstrap test with 90% coverage intervals. We stress that these loadings sizes and signs are relative since we removed the whole-brain mean from the analysis prior to the pattern derivation. Thus, high positive loadings are found in the right mid temporal and inferior parietal cortex, implying relatively higher signal in participants with lower CDR. Bilateral cerebellum and paracentral lobule on the other hand, had relatively lower signal in participants with lower CDR. C. Stratification of the pattern score by APOE status reveals that APOE4 negative patients show the greatest response. APOE ε4 = 0 patients show a treatment effect (left panel), APOE ε4 = 1 do not (right panel).
Fig. 10
Fig. 10
A. Pattern score as function of the 12-month treatment period. The pattern is a linear combination of the first two principal components whose pattern score is slightly but significantly higher for treatment than untreated participants at time point 12 months. B. The left panel shows the pattern score plotted against CDR status (p-level obtained from whole-model F-test.) A higher pattern score implies lower CDR status. The right panel shows loading distributions from a bootstrap test with 90% coverage intervals. We stress that these loadings sizes and signs are relative since we removed the whole-brain mean from the analysis prior to the pattern derivation. Thus, high positive loadings are found in the right mid temporal and inferior parietal cortex, implying relatively higher signal in participants with lower CDR. Bilateral cerebellum and paracentral lobule on the other hand, had relatively lower signal in participants with lower CDR. C. Stratification of the pattern score by APOE status reveals that APOE4 negative patients show the greatest response. APOE ε4 = 0 patients show a treatment effect (left panel), APOE ε4 = 1 do not (right panel).

References

    1. Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, Christensen J, McDade E, Wang G, Xiong C, Cairns NJ, Hassenstab J, Marcus DS, Fagan AM, Jack CR, Hornbeck RC, Paumier KL, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal JP, Correia S, Förster S, Fox NC, Graff-Radford NR, la Fougère C, Levin J, Masters CL, Rossor MN, Salloway S, Saykin AJ, Schofield PR, Thompson PM, Weiner MM, Holtzman DM, Raichle ME, Morris JC, Bateman RJ, Benzinger TLS (2018) Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: A longitudinal study. Lancet Neurol 17, 241–250.
    1. Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, de Leon MJ (2009) FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur J Nucl Med 36, 811–822.
    1. Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20, 148–160.
    1. Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, Higginbotham LA, Guajardo A, White B, Troncoso JC, Thambisetty M, Montine TJ, Lee EB, Trojanowski JQ, Beach TG, Reiman EM, Haroutunian V, Wang M, Schadt E, Zhang B, Dickson DW, Ertekin-Taner N, Golde TE, Petyuk VA, De Jager PL, Bennett DA, Wingo TS, Rangaraju S, Hajjar I, Shulman JM, Lah JJ, Levey AI, Seyfried NT (2020) Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med 26, 769–780.
    1. Gibson GE, Sheu K-FR, Blass JP, Baker A, Carlson KC, Harding B, Perrino P (1988) Reduced Activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 45, 836–840.
    1. Gibson GE, Haroutunian V, Zhang H, Park LCH, Shi Q, Lesser M, Mohs RC, Sheu RKF, Blass JP (2000) Mitochondrial damage in Alzheimer’s disease varies with apolipoprotein E genotype. Ann Neurol 48, 297–303.
    1. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications. Ann Neurol 57, 695–703.
    1. Karnppagounder S, Gibson GE (2009) Thiamine deficiency: A model of metabolic encephalopathy and of selective neuronal vulnerability In Metabolic Encephalopathy, McCandless DW, ed. Springer New York, New York, NY, pp. 235–260.
    1. Calingasan NY, Uchida K,Gibson GE (1999)Protein-bound acrolein. J Neurochem 72, 751–756.
    1. Derk J, MacLean M, Juranek J, Schmidt AM (2018) The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. J Alzheimers Dis Parkinsonism 8, 421.
    1. Chou P-S, Wu M-N, Yang C-C, Shen C-T, Yang Y-H (2019) Effect of advanced glycation end products on the progression of Alzheimer’s disease. J Alzheimers Dis 72, 191–197.
    1. Ataç ZS, Alaylioğlu M, Dursun E, Gezen-Ak D, Yılmazer S, Gürvit H (2019) G82S polymorphism of receptor for advanced glycation end products gene and serum soluble RAGE levels in mild cognitive impairment and dementia of Alzheimer’s type patients in Turkish population. J Clin Neurosci 59, 197–201.
    1. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (2010) The multifaceted therapeutic potential of benfotiamine. Pharmacol Res 61, 482–488.
    1. Raj V, Ojha S, Howarth FC, Belfur PD, Subramanya SB (2018) Therapeutic potential of benfotiamine and its molecular targets. Eur Rev Medl Pharmacol Sci 22, 3261–3273.
    1. Pekovich SR, Martin PR, Singleton CK (1998) Thiamine deficiency decreases steady-state transketolase and pyruvate dehydrogenase but not α-ketoglutarate dehydrogenase mRNA levels in three human cell types. J Nutr 128,683–687.
    1. Ahmed N (2005) Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Res Clin 67, 3–21.
    1. Peyroux J, Sternberg M (2006) Advanced glycation end-products (AGEs): Pharmacological inhibition in diabetes. Pathol Biol 54, 405–419.
    1. Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J (2013) Abnormal thiamine-dependent processes in Alzheimer’s Disease. Lessons from diabetes. Mol Cell Neurosci 55, 17–25.
    1. Gibson GE, Hirsch JA, Fonzetti P, Jordan BD, Cirio RT, Elder J (2016) Vitamin B1 (thiamine) and dementia. Ann NY Acad Sci 1367,21–30.
    1. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG (2008) Benfotiamine in diabetic polyneuropathy (BENDIP): Results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes 116, 600–605.
    1. Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, Ahmed A, Rayman G, Bodmer CW (2007) High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 50, 2164–2170.
    1. Suzuki K, Yamada K, Fukuhara Y, Tsuji A, Shibata K, Wakamatsu N (2017) High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice. PLoS One 12, e0180279.
    1. El-Hattab AW, Zarante AM, Almannai M, Scaglia F (2017) Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab 122, 1–9.
    1. Schmid U, Stopper H, Heidland A, Schupp N (2008) Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro. Diabetes Metab Res Rev 24, 371–377.
    1. Gorlova A, Pavlov D, Anthony DC, Ponomarev ED, Sambon M, Proshin A, Shafarevich I, Babaevskaya D, Lesch K-P, Bettendorff L, Strekalova T (2019) Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice. Neuropharmacology 156, 107543.
    1. Sambon M, Napp A, Demelenne A, Vignisse J, Wins P, Fillet M, Bettendorff L (2019) Thiamine and benfotiamine protect neuroblastoma cells against paraquat and β-amyloid toxicity by a coenzyme-independent mechanism. Heliyon 5, e01710.
    1. Cruz Hernández JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, Kang Y, Cortes-Canteli M, Peyrounette M, Doyeux V, Smith A, Zhou J, Otte G, Beverly JD, Davenport E, Davit Y, Lin CP, Strickland S, Iadecola C, Lorthois S, Nishimura N, Schaffer CB (2019) Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nat Neurosci 22, 413–420.
    1. Shoeb M, Ramana KV (2012) Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic Biol Med 52, 182–190.
    1. Bozic I, Savic D, Laketa D, Bjelobaba I, Milenkovic I, Pekovic S, Nedeljkovic N, Lavrnja I (2015) Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia. PLoS One 10, e0118372–e0118372.
    1. Tapias V, Jainuddin S, Ahuja M, Stack C, Elipenahli C, Vignisse J, Gerges M, Starkova N, Xu H, Starkov AA, Bettendorff L, Hushpulian DM, Smirnova NA, Gazaryan IG, Kaidery NA, Wakade S, Calingasan NY, Thomas B, Gibson GE, Dumont M, Beal MF (2018) Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet 27, 2874–2892.
    1. Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, Sun X, Zhao L, Yu M, Xu Z, Dong W, Qin Y, Fei G, Zhong C, Xu TL (2010) Powerful beneficial effects of benfotiamine on cognitive impairment and β-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain 133, 1342–1351.
    1. Markova N, Bazhenova N, Anthony DC, Vignisse J, Svistunov A, Lesch K-P, Bettendorff L, Strekalova T (2017) Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice. Prog Neuropsychopharmacol 75, 148–156.
    1. Vignisse J, Sambon M, Gorlova A, Pavlov D, Caron N, Malgrange B, Shevtsova E, Svistunov A, Anthony DC, Markova N, Bazhenova N, Coumans B, Lakaye B, Wins P, Strekalova T, Bettendorff L (2017) Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels. Mol Cell Neurosci 82, 126–136.
    1. Haddad M, Perrotte M, Landri S, Lepage A, Fiilop T, Ramassamy C (2019) Circulating and extracellular vesicles levels of N-(1-Carboxymethyl)-L-Lysine (CML) differentiate early to moderate Alzheimer’s disease. J Alzheimers Dis 69, 751–762.
    1. Haddad M, Perrotte M, Khedher MRB, Demongin C, Lepage A, Fülöp T, Ramassamy C (2019) Methylglyoxal and glyoxal as potential peripheral markers for MCI diagnosis and their effects on the expression of neurotrophic, inflammatory and neurodegenerative factors in neurons and in neuronal derived-extracellular vesicles. Int J Mol Sci 20, 4906.
    1. Pan X, Chen Z, Fei G, Pan S, Bao W, Ren S, Guan Y, Zhong C (2016) Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer’s disease. Neurosi Bull 32, 591–596.
    1. Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Götting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D (2006) Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 29, 2064–2071.
    1. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Contributors, Elliott C, Masliah E, Ryan L, Silverberg N (2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14, 535–562.
    1. Rockwood K, Fay S, Gorman M, Carver D, Graham JE (2007) The clinical meaningfulness of ADAS-Cog changes in Alzheimer’s disease patients treated with donepezil in an open-label trial. BMC Neurol 7, 26.
    1. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C (2000) A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 54, 2269.
    1. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.
    1. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 280–292.
    1. Gangolf M, Czerniecki J, Radermecker M, Detry O, Nisolle M, Jouan C, Martin D, Chantraine F, Lakaye B, Wins P, Grisar T, Bettendorff L (2010) Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PLoS One 5, e13616–e13616.
    1. Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA, Reiman EM, Davis MD, Grundman M, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Clark CM, Joshi AD, Mintun MA, Skovronsky DM, Pontecorvo MJ (2012) Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline. Neurol 79, 1636–1644.
    1. Balsis S, Unger AA, Benge JF, Geraci L, Doody RS (2012) Gaining precision on the Alzheimer’s Disease Assessment Scale-cognitive: A comparison of item response theory-based scores and total scores. Alzheimers Dement 8, 288–294.
    1. Weyer G, Erzigkeit H, Kanowski S, Ihl R, Hadler D (1997) Alzheimer’s Disease Assessment Scale: Reliability and validity in a multicenter clinical trial. Int Psychogeriatr 9, 123–138.
    1. Hughes CP, Berg L, Danziger W, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140, 566–572.
    1. Buschke H, Fuld PA (1974) Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 24, 1019.
    1. Fuld PA, Buschke H (1976) Stages of retrieval in verbal learning. J Verb Learning Verb Behav 15, 401–410.
    1. Sliwinski M, Buschke H, Stewart WF, Masur D, Lipton RB (1997) The effect of dementia risk factors on comparative and diagnostic selective reminding norms. J Intl Neuropsychol Soc 3, 317–326.
    1. Cummings JL (1997) The Neuropsychiatric Inventory. Neurology 48, 10S.
    1. Cummings J (2020) The Neuropsychiatric Inventory: Development and applications. J Geriatr Psychiatry Neurol 33, 73–84.
    1. Cummings JL, McPherson S (2001) Neuropsychiatric assessment of Alzheimer’s disease and related dementias. Aging Clin Exp Res 13, 240–246.
    1. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S (1997) An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord 11, S33–S39.
    1. Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD, Alzheimer’s Disease Cooperative Study (2006) ADCS Prevention Instrument Project: Assessment of instrumental activities of daily living for community-dwelling elderly individuals in dementia prevention clinical trials. Alzheimer Dis Assoc Disord 20, S152–S169.
    1. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15, 273–289.
    1. Moeller JR, Strother SC, Sidtis JJ, Rottenberg DA (1987) Scaled subprofile model: A statistical approach to the analysis of functional patterns in positron emission tomographic data. J Cereb Blood Flow Metab 7, 649–658.
    1. Strother SC, Anderson JR, Schaper KA, Sidtis JJ, Liow JS, Woods RP, Rottenberg DA (1995) Principal component analysis and the scaled subprofile model compared to intersubject averaging and statistical parametric mapping: I. “Functional connectivity” of the human motor system studied with [15O]water PET. J Cereb Blood Flow Metab 15, 738–753.
    1. Habeck C, Foster NL, Perneczky R, Kurz A, Alexopoulos P, Koeppe RA, Drzezga A, Stern Y (2008) Multivariate and univariate neuroimaging biomarkers of Alzheimer’s disease. Neuroimage 40, 1503–1515.
    1. Habeck C, Stern Y, Alzheimer’s Disease Neuroimaging Initiative (2010) Multivariate data analysis for neuroimaging data: Overview and application to Alzheimer’s disease. Cell Biochem Biophys 58, 53–67.
    1. Habeck CG (2010) Basics of multivariate analysis in neuroimaging data. J Vis Exp, 1988.
    1. Burnham KP, Anderson DR, Burnham KP (2002) Model selection and multimodel inference a practical information-theoretic approach. Springer, New York.
    1. Efron B (1982) The jackknife, the bootstrap, and other resampling plans. Society for Industrial and Applied Mathematics, Philadelphia.
    1. Efron B, Tibshirani R (1993) An introduction to the bootstrap, Chapman & Hall, New York.
    1. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378, 321–330.
    1. Molnar FJ, Hutton B, Fergusson D (2008) Does analysis using “last observation carried forward” introduce bias in dementia research? Can Med Assoc J 179, 751.
    1. Pan X, Fei G, Lu J, Jin L, Pan S, Chen Z, Wang C, Sang S, Liu H, Hu W, Zhang H, Wang H, Wang Z, Tan Q, Qin Y, Zhang Q, Xie X, Ji Y, Cui D, Gu X, Xu J, Yu Y, Zhong C (2016) Measurement of blood thiamine metabolites for Alzheimer’s disease diagnosis. EBioMedicine 3, 155–162.
    1. Molina JA, Jiménez-Jiménez FJ, Hernánz A, Fernández-Vivancos E, Medina S, de Bustos F, Gómez-Escalonilla C, Sayed Y (2002) Cerebrospinal fluid levels of thiamine in patients with Alzheimer’s disease. J Neural Transm 109, 1035–1044.
    1. Glasø M, Nordbø G, Diep L, Bøhmer T (2004) Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging 8, 407–413.
    1. Sang S, Pan X, Chen Z, Zeng F, Pan S, Liu H, Jin L, Fei G, Wang C, Ren S, Jiao F, Bao W, Zhou W, Guan Y, Zhang Y, Shi H, Wang Y, Yu X, Wang Y, Zhong C (2018) Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not. Alzheimers Res Ther 10, 26.
    1. Mezhenska OA, Aleshin VA, Kaehne T, Artiukhov AV, Bunik VI (2020) Regulation of malate dehydrogenases and glutamate dehydrogenase of mammalian brain by thiamine in vitro and in vivo. Biochemistry (Mosc) 85, 27–39.
    1. Gibson GE, Blass JP (2007) Thiamine-dependent processes and treatment strategies in neurodegeneration. Antioxid Redox Signal 9, 605–1620.
    1. Mkrtchyan G, Aleshin V, Parkhomenko Y, Kaehne T, Luigi Di Salvo M, Parroni A, Contestabile R, Vovk A, Bettendorff L, Bunik V (2015) Molecular mechanisms of the non-coenzyme action of thiamin in brain: Biochemical, structural and pathway analysis. Sci Rep 5, 12583.
    1. Von Muralt A (1958) The role of thiamine (vitamin B1) in nervous excitation. Exp Cell Res 14, 72–79.
    1. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FRJ, Visser PJ, and the Amyloid Biomarker Study G (2015) Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis. JAMA 313, 1924–1938.
    1. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90, 9649–9653.
    1. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: Allelic variation and receptor interactions. Neuron 11, 575–580.
    1. Deo P, Dhillon VS, Chua A, Thomas P, Fenech M (2019) APOE ε4 carriers have a greater propensity to glycation and sRAGE which is further influenced by RAGE G82S polymorphism. J Gerontol A Biol 75, 1899–1905.
    1. Meli M, Perier C, Ferron C, Parssegny F, Denis C, Gonthier R, Laurent B, Reynaud E, Frey J, Chamson A (2002) Serum pentosidine as an indicator of Alzheimer’s disease. J Alzheimers Dis 4, 93–96.
    1. Arnold M, Nho K, Kueider-Paisley A, Massaro T, Huynh K, Brauner B, MahmoudianDehkordi S, Louie G, Moseley MA, Thompson JW, John-Williams LS, Tenenbaum JD, Blach C, Chang R, Brinton RD, Baillie R, Han X, Trojanowski JQ, Shaw LM, Martins R, Weiner MW, Trushina E, Toledo JB, Meikle PJ, Bennett DA, Krumsiek J, Doraiswamy PM, Saykin AJ, Kaddurah-Daouk R, Kastenmiiller G (2020) Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome. Nat Commun 11, 1148.
    1. Depeint F, Shangari N, Furrer R, Bruce WR, O’Brien PJ (2007) Marginal thiamine deficiency increases oxidative markers in the plasma and selected tissues in F344 rats. Nutr Res 27, 698–704.
    1. Goldin A, Beckman Joshua A, Schmidt Ann M, Creager Mark A (2006) Advanced glycation end products. Circulation 114, 597–605.
    1. Hammes H-P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9, 294–299.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner