Neurocognitive outcomes in homocysteine lowering trials

Transcription

1 Neurocognitive outcomes in homocysteine lowering trials خفض الهوموسيستي ين والتا ثيرات العصبيه -الا دراكيه Aron Troen, DPhil Director, Nutrition and Brain Health Laboratory Institute of Biochemistry Food & Nutrition Science The Hebrew University of Jerusalem Visiting Scientist, Neuroscience and Aging Laboratory USDA Human Nutrition Research Center on Aging Tufts University, Boston MA, USA ICAD-ME, Abu Dhabi, UAE,

2 Evidence Based Medicine Meta Analysis Randomized Controlled Trials Prospective Cohort Studies Case Control and Cross Sectional Studies Basic research, in vitro and pre clinical in vivo Studies

3 Poor B-vitamin status and high homocysteine are associated with cognitive impairment Study type Positive finding Negative finding Cross-sectional Prospective 77 Studies 34,238 Subjects 13 Studies 7,196 Subjects 7 Studies 3,645 Subjects 3 Studies 1,722 Subjects Smith, AD. Food and Nutrition Bulletin, 2008

4 Homocysteine is a potentially modifiable risk factor for dementia and cerebrovascular disease The Framingham Study Seshadri et al. NEJM, 2002 Cumulative Incidence thcy Q1-3 thcy Q M (Age 65 90) Years

5 Dementia is Multifactorial Preclinical: Microvascular dysfunction (nianirs); Amyloid accumulation (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI); Tau-mediated neuronal injury (CSF) Mild Cognitive Impairment: Brian Atrophy (MRI); Cognition Dementia: Clinical Disease (After Sperling 2011 with the addition of microvascular dysfunction)

6 Can Vascular Cognitive Risk be Modified Age Vascular Risk Early Vascular Changes? Modifiable Cognitive Risk Hypertension Hypercholesterolemia Hyperhomocysteinemia Metabolic Syndrome Atherosclerosis Arteriosclerosis LVD / SVD Subcortical VaD (Lacunes Silent Infarcts) WML CAA Microbleeds Microinfarcts Hypoperfusion BBB leakiness Inflammation End Stage Vascular Pathology Normal Prodromal MCI Dementia

7 Homocysteine & B-vitamin metabolism Folic Acid X SAM Methionine H 4 Folate Methylation DNA Neurotransmitters Hormones Proteins Enzymes Phospholipids PtdCholine Choline Betaine B12 DNA Synthesis Acetylcholine XCH 3 SAH CH 3 H 4 Folate B6

8 Unified hypothesis: Low normal intake or blood concentrations of B vitamins (folate, B 12 and B 6 ) and/or moderately elevated plasma total homocysteine increase the risk of brain vascular and neurodegenerative damage and developing cognitive impairment in the elderly Smith, AD. Food and Nutrition Bulletin, 2008: 29; S143 S172 Selhub et al., Am J Clin Nutr Feb;71(2):614S 620S. Rosenberg and Miller. Am J Clin Nutr Jun;55(6):1237S 1243S Multiple, theoretically plausible, non exclusive, mechanisms (Causality) Corollary risk may be reduced by vitamin supplementation (Efficacy)

9 B vitamins slow rate of brain atrophy in MCI patients in VITACOG trial folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d) N=187 Age >70 Duration 24 months Oxford (no folate fortification)

10 Baseline thcy determines response 10

11 Cognitive Protection by B vitamins depends on baseline Homocysteine

12 Atrophy prevention by B vitamins depends on plasma Omega 3 Fatty Acids Placebo B VITAMINS Jerneren et al, AJCN, 2015

13 Folic Acid improved selected cognitive outcomes in the FACIT trial * * * * FA Placebo Durga et al., Lancet 2006

14 B vitamin therapy lowers homocysteine and improves selective cognitive outcomes in the randomized FAVORIT Ancillary Cognitive Trial Tammy M. Scott; Gail Rogers; Daniel E. Weiner; Kara Livingston; Jacob Selhub ; Paul F. Jacques; Irwin H. Rosenberg ; & Aron M. Troen; for the FACT Study Investigators Eligibility Methods in Brief Age Stable kidney allograft for at least 6 months Elevated thcy 12.0 µmol/l for men or 11.0 µmol/l for women Not visually or hearing impaired (capable of cognitive testing) Recruited from 18 sites in North America and Canada between 2002 and 2007 Intervention Control: 0 mg Folic Acid 2 µg Vitamin B mg Vitamin B6 Treatment: 5 mg Folic Acid 1000 µg Vitamin B mg Vitamin B6 (Submitted)

15 Cognitive Tests

16 Enrollment & Flow FAVORIT cohort n=4,110 FACT cohort in USA & Canada total subject enrolled for in person testing n=584 Total subjects treated at least 6 months before follow up testing n=547 Subjects with complete data for cross sectional end of trial ITT analysis n=524 Comparison of cognition by treatment on last available test ITT comparison of change over time (last test baseline test ) Treatment n=250 Treatment arm subset with baseline data for longitudinal ITT analysis n=60 Control n=274 Control arm subset with baseline data for longitudinal ITT analysis n=71

17 Baseline Characteristics

18 Prevalence of Cognitive Impairment at Trial End % Impaired Subjects * Rx 15 Placebo

19 Change in Cognitive Score Between 1 st and Last Test Point Change in Score * Rx Placebo

20 Meta analysis of B vitamintrials argues for lack of efficacy Clarke et al., Am J Clin Nutr Aug; 100(2):

21 Problem: Considerable heterogeneity in results of RCTs 584 YES

22 Fortification dramatically improved folate status in the Framingham Offspring Cohort Pre Post Plasma Folate (ng/ml) From Jacques et al NEJM 1999;340:

23 Fortification increased the prevalence of excess folate intake > UL (1 mg/day) * 12 Prevalence % Non Supplement Users Supplement Users 0 Before fortification After fortification Before fortification After fortification

24 More folate might not be better Risk of cognitive impairment Risk Odds Ratio (95%CI) Folate B (ref) Normal High Normal High Normal Normal Low Low N = 826 (63%) 180 (14%) 253 (19%) 42 (3%) 4.9 Protection Selhub J et al. Am J Clin Nutr. 2009;89(2):702S 706S.

25 Higher Dietary Folate Intake Predicts Faster Cognitive Decline Among Community-Dwelling Older Persons Slope of 6 year cognitive decline µg supplemental folic acid per day P for trend < Morris MC, et al., Arch Neurol. 2005;62(4): *

26 Key findings for cognition in the multivariate regression: High Folate (>17.8 ng/ml) was associated with better memory (4 5th quintiles vs. 1st 3rd quintiles; β=0.22, P<0.01). Carriers of the DHFR de/del genotype had worse cognition vs. non carriers Memory (β= 0.22, P<0.05) Executive Function (β= 0.19, P<0.05) Carriers of the del/del genotype with high folate had significantly worse memory scores than both non carriers with high folate and del/del carriers with normal folate (β for interaction term=0.26, P<0.05).

27 High Folate Predicts Better Memory on Average

28 But High Folate x del/del Genotype Predicts Poor Memory

29 WAFACS trial results: crossover in placebo arm and possible excess in treatment arm Baseline N cases Placebo Rx <7 7 <15 15 < >40 Follow up 80 Placebo Rx <7 7 <15 15 < >40 Deficient (?) Adequate (?) Excess(?) Folate ng/ml (Adapted from Albert et al JAMA 2008)

30 The Vitamin Intervention for Stroke Prevention Trial (VISP) Objective: Effect of Hcy lowering on recurrent stroke reduction N = 3680 patients with nondisabling cerebral infarction Mean age 66.2 years Treatment: High dose: 25mg B6; 2.5mg FA, 400 mcg B12 Low doses: 0.2mg B6; 0.02 mg FA; 6 mcg B12 NEGATIVE Primary outcome: Recurrent Stroke, Myocardial Infarction & Death Toole NEJM 2004

31 The Vitamin Intervention for Stroke Prevention Trial An Efficacy Analysis: B12 treatment may prevent stroke 100% 95% 90% 85% Group Baseline B12 >= median: Low dose High Dose Baseline B12 < median: Low dose High Dose 80% Spence et al, Stroke 2005;36:

32 Randomized Nutrition RCTs are Different from Drug RCTs: Both randomize to Control and R x arms to minimize confounding and bias Both have potential for selection bias and problems of generalizability Drug and supplement trials are blinded but it isn t practical in dietary trials Prevention (Risk Reduction) rather than Therapy (Disease Modifying) Nutrition trials often conflate Efficacy with Causality Rational Drug Target Mechanism vs. Risk Reduction / pleiotropic response to metabolic shift GRAS compounds with no dose finding, PK and PD studies Ethics: If it is regarded as safe, can we deny treatment and assign a placebo? Modify natural exposure rather than expose to an exogenous compound Public Health rather than clinical orientation: Small effect X large (preclinical) populations vs. large effects X smaller diseased population Rely on public vs. private funding Different Regulatory Considerations

33 Should we challenge the dogma of EBM? Can we accept a different standard of evidence? Should we use metabolic dose response rather than ITT efficacy studies? Should we use Bradford Hill criteria to guide practice rather than RCTs?

34 Conclusions Homocysteine and B vitamins Elevated circulating homocysteine is an important prognostic risk factor for cerebrovascular and neurodegenerative disease. Indiscriminate vitamin therapy is unlikely to help and may cause harm. Specific populations might benefit but have yet to be clearly defined, but B vitamin repletion is likely beneficial. Clarifying the metabolic conditions & interactions that determine response to treatment will yield better formulations and opportunities for intervention.

35 The Way Forward? Develop targeted multi modal nutritional/lifestyle interventions Focus on Risk Reduction and Prevention Integrate observational evidence with alternative, rational, ethical, trial desings to evaluate evidence and guide clinical and public health practice Invest & Collborate!

36 Evidence Based Medicine Meta Analysis Randomized Controlled Trials Prospective Studies Case Control and Cross Sectional Studies Basic research, in vitro and pre clinical in vivo Studies

37 Evidence Based Prevention Medical Practice Synthesis & Integration Pre clinical Research Epidemiological Observation Risk Clinical Trials Efficacy Systematic Review & Meta Analysis

38 NBHL Hebrew University Nur Abu Ahmad Amir Bross Emil Mahamid Yael Yellin Ghada Baransi Dana Philip Shani Martsiano Vered Vayman Shani Blumenriech Merav Reizman Nathalie Weizmann Lior Chatow Tufts University Irwin Rosenberg Tammy M. Scott Paul Jacques Jacob Selhub Kara Knightly Daniel Weiner Jose Ordovas Chao Qiang Lai Laurence Parnell Denish Moorthy