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Geriatrics 2019, 4(1), 31; https://doi.org/10.3390/geriatrics4010031

Article
Neurocognitive Function and Quality of Life Outcomes in the ONTRAC Study for Skin Cancer Chemoprevention by Nicotinamide
1
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2006, Australia
2
Centre for Medical Psychology & Evidence-Based Decision-Making, University of Sydney, Sydney, NSW 2006, Australia
3
Sydney Medical School, Concord Clinical School, University of Sydney, Sydney, NSW 2006, Australia
4
Concord Repatriation General Hospital, Sydney Concord, NSW 2139, Australia
5
Dermatology and Bosch Institute, University of Sydney at Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
6
Dermatology, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
7
Melanoma Institute Australia, North Sydney, Wollstonecraft, NSW 2065, Australia
*
Author to whom correspondence should be addressed.
Received: 31 January 2019 / Accepted: 22 March 2019 / Published: 25 March 2019

Abstract

:
Nicotinamide (vitamin B3) has photoprotective effects and reduces skin cancer incidence in high risk patients. Nicotinamide also improves cognition in animal models. As part of the ONTRAC (Oral Nicotinamide To Reduce Actinic Cancer) phase III placebo-controlled, randomized trial to assess nicotinamide’s efficacy in skin cancer prevention, we included clinical neurocognitive function and patient-reported quality of life assessments at baseline and after 12 months of intervention in individuals with previous skin cancer in order to assess any effect of oral nicotinamide (500 mg po twice daily) on cognitive function and quality of life. In our sample of 310 participants who completed neurocognitive function testing at baseline and at 12 months, we were not able to detect any significant effect of oral nicotinamide on cognitive function nor on quality of life. Further studies of nicotinamide’s effects on cognition in humans might include individuals with pre-existing mild cognitive impairment, and it may be that higher doses of nicotinamide are required to significantly influence cognitive function compared to doses required to reduce skin cancer.
Keywords:
vitamin B3; cognitive aging; prevention

1. Introduction

As a precursor of nicotinamide adenine dinucleotide (NAD+), nicotinamide (vitamin B3) plays a central role in cellular energy metabolism. In the skin, nicotinamide is able to replenish cellular energy after ultraviolet radiation exposure [1], thereby enhancing the highly energy-dependent process of epidermal DNA repair [2]. Nicotinamide additionally has immune protective [3] and anti-inflammatory effects [4] which suggest its potential for skin cancer chemoprevention. Our multicenter phase III double-blind, randomised placebo-controlled trial (ONTRAC; Oral Nicotinamide to Reduce Actinic Cancer) found that oral nicotinamide (vitamin B3) significantly reduced the incidence of nonmelanoma skin cancer (basal cell and squamous cell carcinoma) by 23% relative to a placebo in a high risk population [5] (Australian New Zealand Clinical Trials Registry number ACTRN12612000625875).
Secondary pre-specified objectives of ONTRAC included an evaluation of the effect of oral nicotinamide on neurocognitive function (NCF) and quality of life (QoL). The NCF objective was pursued given the evidence for the role of nicotinamide in cognitive and neurological function available at the time ONTRAC was designed. In mice, exposure to nicotinamide has been associated with improved short term memory [6], reduced cognitive decline in an Alzheimer’s model [6], and improved recovery from cortical contusion injury [7]. Nicotinamide has also been used as a neuroprotective agent in mouse models of stroke [7] where it is thought to act by increasing intracellular energy (adenosine triphosphate) [8]. In humans, lower dietary nicotinamide has been associated with increased dementia risk [9], and dementia is a known symptom of nicotinamide deficiency (pellagra) [10].

2. Results

Of the 386 patients randomized to ONTRAC, 310 and 290 took part in the NCF and QoL substudies respectively (Supplementary Figures S1 and S2). Substudy participants had comparable characteristics to the entire ONTRAC population (Comparison for NCF substudy shown in Table 1). The mean age of participants in the NCF substudy was 66 years (range 30–91); 37% were female. The mean baseline and change from baseline to month 12 scores are shown in Table 2 along with the estimated treatment effect from the linear model.
There were no differences between the arms in any neuropsychological test at baseline. All mean scores were within the expected range with the exception of verbal memory and learning in which both groups scored 1SD below the expected mean. There was no difference between the arms in the change score from baseline to 12 months, with the exception of the Digit span assessment which yielded a p-value below 0.05; however, this result remained consistent with the play of chance when taking into account the multiple comparisons performed. There was no difference between the arms in cognitive symptoms or in any of the QoL domains at any time point.

3. Discussion

In our cohort of largely elderly, community dwelling skin cancer patients assessed over a 12-month intervention period, there was no compelling statistical evidence of an effect of nicotinamide on neurocognitive performance nor on QoL. The narrow width of the confidence intervals helps rule out the plausibility of nicotinamide causing a clinically important reduction in NCF or QoL. The effects of nicotinamide on NCF in individuals at higher risk of progression to dementia, for example those with early cognitive impairment but not frank dementia, is currently unknown. There are, as of yet, no published studies of nicotinamide use in this setting, nor as a preventive agent in individuals without cognitive deficit. Whilst some patients with Alzheimer’s Disease given nicotinamide adenine dinucleotide (NADH; 10mg daily) did show improvement in mini mental state examination and global deterioration scores [11], others did not [12]. Nicotinamide derivatives such as nicotinamide mononucleotide, nicotinamide riboside [13] and nicotinamide loaded lipid nanoparticles [14] have, at extremely high doses, shown some cognitive benefits in Alzheimer’s disease animal models and in aged mice but their effects on cognition in humans, and at tolerable doses, are unknown [15].

4. Materials and Methods

Details of the design of the ONTRAC trial (Australian New Zealand Clinical Trials Registry number ACTRN12612000625875) have been published previously [5]. Immune-competent, community dwelling adults with at least two histologically confirmed nonmelanoma skin cancers in the past 5 years were randomized to receive nicotinamide 500 mg or placebo twice daily (with or without food) for 12 months. Participants were stratified by gender, study site and by number of nonmelanoma skin cancers in the previous five years (≤5 or ≥6). Participation of ONTRAC patients in the NCF and QoL substudies was not mandatory, and eligibility required spoken and written English language skills equivalent to year 8 to complete the neuropsychological assessments. Assessments were administered at baseline and month 12 by trained research assistants.
The NCF substudy assessed verbal learning and memory, verbal and written word fluency, information processing, attention/working memory, and executive function using the following battery of instruments: Hopkins Verbal Learning Test-Revised (HVLT-R) [16], Controlled Oral Word Association (COWA) [17], Written Word Fluency [18], Stroop Color and Word Test [19], Trail Making Test Part A and B [20], and the Wechsler Memory Scale-Third edition WMS-III Digit Span [21]. Cognitive symptoms were evaluated using the European Organisation for Research and Treatment of Cancer Quality of life questionnaire (EORTC-QLQ-C30) Cognitive Functioning scale [22].
The QoL substudy used a selection of scales from the Patient Reported Outcomes Measurement Information System Computer Adaptive Test (PROMIS-CAT) system [23] including Global Health (mental and physical), Anxiety, Depression, Fatigue, Applied Cognitive Abilities, and Applied Cognitive General Concerns.
Raw neuropsychological scores were converted to demographically-corrected T scores (based on age, sex, education, and ethnicity) [24] with an expected mean of 50 and standard deviation of 10. Comparisons between treatment arms at 12 months on the scaled scores from these assessments were performed, as specified a priori in the ONTRAC analysis plan [5], using a linear model with the baseline value, treatment allocation, and centre fitted as covariates.

5. Conclusions

Nicotinamide at a dose of 500 mg twice daily for 12 months did not significantly alter neurocognitive function in our participants. It may be that higher nicotinamide doses than our skin cancer chemoprevention dose, administered over a longer duration, are needed to elicit beneficial effects on NCF.

Supplementary Materials

The following are available online at https://www.mdpi.com/2308-3417/4/1/31/s1. Figure S1: CONSORT diagram for neurocognitive function (NCF) testing of ONTRAC participants; Figure S2: CONSORT diagram for Quality of Life (QoL) assessment of ONTRAC participants.

Author Contributions

Conceptualization, H.M.D., J.L.V., D.L.D. and A.C.C.; methodology, A.J.M., H.M.D., J.L.V; validation, C.R., A.D. and A.J.M.; formal analysis, A.J.M., H.M.D., J.L.V., A.D., C.R.; investigation, R.A.D., B.C., P.F.-P., G.S.G., N.C., A.C.C.; data curation, A.J.M., D.L.D.; writing—original draft preparation, D.L.D.; writing—review and editing, A.J.M., H.M.D., J.L.V., R.A.D., B.C., P.F.-P., A.D., C.R., G.S.G., N.C., G.M.H., D.L.D., A.C.C.; visualization, H.M.D., J.L.V., G.M.H., D.L.D., A.C.C.; supervision, H.M.D., J.L.V., P.F.-P., D.L.D.; project administration, D.L.D.; funding acquisition, A.J.M., P.F.-P., G.M.H., D.L.D.

Funding

This research was funded by National Health & Medical Research Council Project Grant 1026977.

Acknowledgments

We are most grateful to our study participants for their generous participation in this project. We thank Blackmores Ltd. (Warriewood, NSW, Australia) for supply of the placebo and nicotinamide tablets.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Park, J.; Halliday, G.M.; Surjana, D.; Damian, D.L. Nicotinamide prevents ultraviolet radiation-induced cellular energy loss. Photochem. Photobiol. 2010, 86, 942–948. [Google Scholar] [CrossRef] [PubMed]
  2. Surjana, D.; Halliday, G.M.; Damian, D.L. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin. Carcinogen 2013, 34, 1144–1149. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Yiasemides, E.; Sivapirabu, G.; Halliday, G.M.; Park, J.; Damian, D.L. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogen 2009, 30, 101–105. [Google Scholar] [CrossRef] [PubMed]
  4. Ungerstedt, J.S.; Blomback, M.; Soderstrom, T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin. Exp. Immunol. 2003, 131, 48–52. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Chen, A.C.; Martin, A.J.; Choy, B.; Fernandez-Penas, P.; Dalziell, R.A.; McKenzie, C.A.; Scolyer, R.A.; Dhillon, H.M.; Vardy, J.L.; Kricker, A.; et al. A Phase 3 Randomized Trial of Nicotinamide for Skin Cancer Chemoprevention. N. Engl. J. Med. 2015, 373, 1618–1626. [Google Scholar] [CrossRef] [PubMed]
  6. Green, K.N.; Steffan, J.S.; Martinez-Coria, H.; Sun, X.; Schreiber, S.S.; Thompson, L.M.; LaFerla, F.M. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J. Neurosci. 2008, 28, 11500–11510. [Google Scholar] [CrossRef] [PubMed]
  7. Goffus, A.M.; Anderson, G.D.; Hoane, M. Sustained delivery of nicotinamide limits cortical injury and improves functional recovery following traumatic brain injury. Oxid. Med. Cell. Longev. 2010, 3, 145–152. [Google Scholar] [CrossRef] [PubMed][Green Version]
  8. Tam, D.; Tam, M.; Maynard, K.I. Nicotinamide modulates energy utilization and improves functional recovery from ischemia in the in vitro rabbit retina. Ann. N. Y. Acad. Sci. 2005, 1053, 258–268. [Google Scholar] [CrossRef] [PubMed]
  9. Morris, M.C.; Evans, D.A.; Bienias, J.L.; Scherr, P.A.; Tangney, C.C.; Herbert, L.E.; Bennet, D.A.; Wilson, R.S.; Aggarwal, N. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J. Neurol. Neurosurg. Psychiatry 2004, 75, 1093–1099. [Google Scholar] [CrossRef] [PubMed]
  10. Hegyi, J.; Schwartz, R.A.; Hegyi, V. Pellagra: Dermatitis, dementia and diarrhea. Int. J. Dermatol. 2004, 43, 1–5. [Google Scholar] [CrossRef] [PubMed]
  11. Birkmayer, J.G.D. Coenzyme nicotinamide adenine dinucleotide—New therapeutic approach for improving dementia of the Alzheimer type. Ann. Clin. Lab. Sci. 1996, 26, 1–9. [Google Scholar] [PubMed]
  12. Rainer, M.; Kraxberger, E.; Haushofer, M.; Mucke, H.A.; Jellinger, K.A. No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia. J. Neural Transm. 2000, 107, 1475–1481. [Google Scholar] [CrossRef] [PubMed]
  13. Xie, X.; Gao, Y.; Zeng, M.; Wang, Y.; Wei, T.F.; Lu, Y.B.; Zhang, W.P. Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice. Metab. Brain Dis. 2019, 34, 353–366. [Google Scholar] [CrossRef] [PubMed]
  14. Vakilinezhad, M.A.; Amini, A.; Akbari Javar, H. Baha’addini Beigi Zarandi BF, Montaseri H, Dinarvand R: Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer’s disease animal model by reducing Tau hyperphosphorylation. Daru 2018, 26, 165–177. [Google Scholar] [CrossRef] [PubMed]
  15. Braidy, N.; Grant, R.; Sachdev, P.S. Nicotinamide adenine dinucleotide and its related precursors for the treatment of Alzheimer’s disease. Curr. Opin. Psychiatry 2018, 31, 160–166. [Google Scholar] [CrossRef] [PubMed]
  16. Benedict, R.H.B.; Schretlen, D.; Groninger, L.; Brandt, J. Hopkins Verbal Learning Test-Revised: Normative data and analysis of inter-form and test-retest reliability. Clin. Neuropsychol. 1998, 12, 43–55. [Google Scholar] [CrossRef]
  17. Benton, A.L.; Hamsher, K.D.S. Multilingual Aphasia Examination; AJA Associates: Iowa City, IA, USA, 1989. [Google Scholar]
  18. Strauss, E.; Sherman, E.M.S.; Spreen, O. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, 3rd ed.; Oxford University Press Inc.: New York, NY, USA, 2006. [Google Scholar]
  19. Stroop, J.R. Studies of interference in serial verbal reactions. J. Exp. Psychol. 1935, 18, 643–662. [Google Scholar] [CrossRef]
  20. Reitan, R.M. Trail Making Test Manual for Administration and Scoring; Reitan Neuropsychology Laboratory: Tucson, AZ, USA, 1992. [Google Scholar]
  21. Wechsler Memory Scale—Third Edition WMS-III Digit Span Administration and Scoring Manual; The Psychological Corporation (PAR) Inc.: Lutz, FL, USA, 2002.
  22. Jacobs, S.R.; Jacobsen, P.B.; Booth-Jones, M.; Wagner, L.I.; Anasetti, C. Evaluation of the functional assessment of cancer therapy cognitive scale with hematopoietic stem cell transplant patients. J. Pain Symptom Manag. 2007, 33, 13–23. [Google Scholar] [CrossRef] [PubMed]
  23. Cella, D.; Yount, S.; Rothrock, N.; Gershon, R.; Cook, K.; Reeve, B.; Ader, D.; Fries, J.F.; Bruce, B.; Rose, M. The Patient-Reported Outcomes Measurement Information System (PROMIS): Progress of an NIH Roadmap cooperative group during its first two years. Med. Care 2007, 45 (Suppl. 1), S3–S11. [Google Scholar] [CrossRef] [PubMed]
  24. Heaton, R.K.; Taylor, M.J. Revised Comprehensive Norms for an Expanded Halstead-Reitan Battery: Professional Manual; Psychological Assessment Resources, Inc.: Odessa, FL, USA, 2004. [Google Scholar]
Table 1. Baseline characteristics.
Table 1. Baseline characteristics.
CharacteristicNCF Subgroup *All ONTRAC Patients
Nicotinamide
N = 152
Placebo
N = 158
Nicotinamide
N = 193
Placebo
N = 193
Age Mean (SD)66.3 (11.0)65.8 (11.7)66.4 (11.8)66.4 (11.8)
Female55 (36.2%)60 (38.0%)71 (36.8%)72 (37.3%)
Years of education (SD)13.0 (4.0)12.7 (4.1)12.5 (4.0)12.6 (4.4)
Never smoked72 (47.4%)75 (47.5%)92 (47.7%)88 (45.6%)
NMSCs in previous 5 years Mean (SD)8.2 (8.7)8.3 (7.4)7.9 (8.0)8.2 (7.4)
Hypertension68 (44.7%)70 (44.3%)86 (44.6%)84 (43.5%)
Hypercholesterolaemia63 (41.4%)60 (38.0%)79 (40.9%)82 (42.5%)
Asthma28 (18.4%)19 (12.0%)37 (19.2%)21 (10.9%)
Ischaemic heart disease23 (15.1%)18 (11.4%)32 (16.6%)23 (11.9%)
Osteoporosis11 (7.2%)15 (9.5%)19 (9.8%)20 (10.4%)
Cancer (other than skin)9 (5.9%)8 (5.1%)14 (7.3%)10 (5.2%)
Diabetes11 (7.2%)12 (7.6%)16 (8.3%)15 (7.8%)
Stroke/TIA5 (3.3%)12 (7.6%)5 (2.6%)13 (6.7%)
NCF, neurocognitive function; NMSCs, nonmelanoma skin cancers; TIA, transient ischaemic attack. * Values for patients that contributed both baseline and month 12 data shown.
Table 2. NCF and QoL Substudy Results.
Table 2. NCF and QoL Substudy Results.
ScaleNicotinamide
Mean (SD)
Placebo
Mean (SD)
Estimated
Effect (95% CIs)
NCF SubstudyN = 152 *N = 158 *
Cognitive Domain
 Test
Verbal Learning and Memory
 HVLT-R Total recall
 Baseline 39.68 (10.76) 40.06 (11.42)
 Change to Month 12 6.03 (9.64) 4.54 (10.97)1.22 (−0.79 to 3.23; p = 0.23)
 HVLT-R Delayed recall
 Baseline 37.41 (12.61)38.67 (12)
 Change to Month 12 5.5 (10.25)3.77 (9.47)1.29 (−0.75 to 3.33; p = 0.22)
Verbal Fluency
 COWA Total letter fluency
 Baseline 51.45 (12.02) 51.18 (13.39)
 Change to Month 12 2.37 (7.5) 1.85 (8.02)0.54 (−1.15 to 2.22; p = 0.53)
 COWA Category fluency—animal
 Baseline 50.86 (10.22) 51.05 (10.29)
 Change to Month 12 0.41 (9.39) 1.3 (10.69)−1.00 (−2.89 to 0.89; p = 0.30)
Written Fluency
 Baseline54.32 (10.92)52.24 (11.78)
 Change to Month 121.63 (6.07)1.68 (6.18)0.14 (−1.22 to 1.50; p = 0.84)
Executive Function
 Trails B
 Baseline54.37 (9.51)54.7 (9.06)
 Change to Month 121.24 (7.92)0.8 (7.85)0.30 (−1.32 to 1.93; p = 0.71)
Stroop Colour-Word
 Baseline 49.32 (8.5) 50.4 (9.11)
 Change to Month 12 0.15 (5.41) 0.25 (5.15)−0.34 (−1.48 to 0.80; p = 0.56)
 Colour-word (inference)
 Baseline 46.29 (7.69) 46.76 (6.92)
 Change to Month 12 0.23 (5.91) 0.11 (5.13)−0.10 (−1.2 to 1.00; p = 0.86)
Attention
 Digit span total
 Baseline56.97 (10.26)56.1 (10.02)
 Change to Month 122.39 (6.54)0.63 (7.39)1.90 (0.40 to 3.39; p = 0.01)
Information Processing
 Trails A
 Baseline 50.81 (8.38)50.93 (9.69)
 Change to Month 12 1.59 (7.84)1.52 (8.72)0.00 (−1.64 to 1.65; p = 1.00)
Symptoms
 QLQ-C30-Cog. Functioning
 Baseline76.32 (22.16)73.99 (17.43)
 Change to Month 121.97 (18.79)1.06 (19.31)2.03 (−1.42 to 5.50; p = 0.25)
QoL SubstudyN = 143 *N = 146 *
 Scale
 Global Mental Health
 Baseline52.04 (8.41)51.69 (7.89)
 Change to Month 12−0.31 (5.73)−0.38 (6.57)0.12 (−1.26 to 1.50; p = 0.87)
 Global Physical Health
 Baseline52.98 (8.01)51.31 (7.44)
 Change to Month 12−1.12 (5.76)−0.87 (5.63)0.10 (−1.18 to 1.38; p = 0.88)
 Anxiety
 Baseline50.02 (7.96)50.21 (7.66)
 Change to Month 120.12 (6.41)0.90 (6.88)−0.81 (−2.25 to 0.62; p = 0.27)
 Depression
 Baseline47.51 (8.03)47.99 (7.11)
 Change to Month 120.86 (6.56)0.80 (6.51)−0.10 (−1.49 to 1.29; p = 0.89)
 Fatigue
 Baseline47.62 (8.57)49.13 (7.68)
 Change to Month 120.33 (7.10)0.09 (6.90)−0.28 (−1.77 to 1.21; p = 0.71)
 Applied Cog Abilities
 Baseline51.68 (6.69)50.11 (6.40)
 Change to Month 12−0.90 (6.53)0.17 (6.87)−0.31 (−1.70 to 1.08; p = 0.66)
 Applied Cog General Concerns
 Baseline33.81 (9.27)35.75 (8.19)
 Change to Month 12−0.45 (8.83)−0.19 (8.16)−1.15 (−2.89 to 0.59; p = 0.19)
* Values for patients that contributed at least one scale score at both baseline and month 12 data shown. Change in score is the difference between the baseline score and the 12 month score. Estimates from a linear model with the baseline value, treatment allocation, and centre fitted as covariates. COWA = Controlled Oral Word Association (of the Multilingual Aphasia Examination); Digit span = Wechsler Memory Scale—Third edition Digit Span; Hopkins Verbal Learning Test-Revised = HVLT-R; Trails A = Trail Making Test Part A; Trails B = Trail Making Test Part B.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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