Interação do fator neurotrófico encefálico com o estresse oxidativo: abordagem neuropatológica a um potencial biomarcador da doença de Alzheimer

Shen, Robert; Ardianto, Christian; Celia, Celia; Sidharta, Veronika Maria; Sasmita, Poppy Kristina; Satriotomo, Irawan; Turana, Yuda

Robert Shen

conceptualization

editing

visualization

writing – original draft

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0002-2063-4145

Christian Ardianto

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0002-0456-6736

Celia Celia

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0002-6330-9131

Veronika Maria Sidharta

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0002-9982-6528

Poppy Kristina Sasmita

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0002-4859-3402

Irawan Satriotomo

writing – review & editing

University of Florida, Gainesville, Department of Neurology, Florida, USA.

Satriotomo Foundation, Indonesia Neuroscience Institute, Jakarta, Indonesia.

http://orcid.org/0000-0003-0519-9509

Yuda Turana Correspondence: Yuda Turana; Email: yuda.turana@atmajaya.ac.id.

conceptualization

editing

funding acquisition

visualization

writing – review & editing

Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia.

http://orcid.org/0000-0003-4527-0285

Correspondence: Yuda Turana; Email: yuda.turana@atmajaya.ac.id.

Disclosure: The authors report no conflicts of interest.

Reference	Size (n) and Design	Diseases	Key findings
Yasutake et al.¹²⁵125 Yasutake C, Kuroda K, Yanagawa T, Okamura T, Yoneda H. Serum BDNF, TNF-alpha and IL-1beta levels in dementia patients: comparison between Alzheimer’s disease and vascular dementia. Eur Arch Psychiatry Clin Neurosci. 2006;256(7):402-6. https://doi.org/10.1007/s00406-006-0652-8 https://doi.org/10.1007/s00406-006-0652-...	60 AD, 60 VaD, 33 healthy elderly controls. Cross-sectional.	AD and VaD	Serum BDNF levels are significantly lower in AD groups than in VaD and controls group. BDNF plays pathological roles in AD, but further investigation is needed.
Laske et al.¹²⁶126 Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, et al. Stage-dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm (Vienna). 2006;113(9):1217-24. https://doi.org/10.1007/s00702-005-0397-y https://doi.org/10.1007/s00702-005-0397-...	15 early stages AD, 15 severe stages AD, 10 healthy elderly controls. Cross-sectional.	AD	Serum BDNF levels increased in the early stages of AD, reflecting the compensatory mechanism of early neurodegeneration, while in time, they will decrease, correlating with the severity of AD because of trophic support lacking and increasing Aβ plaque accumulation contributing to specific progressive degeneration in the affected brain region. BDNF in both groups is not detected in CSF because its level is below the detection limit. Further investigation is needed to define BDNF as an AD clinical diagnosis marker and for therapeutic monitoring.
Laske et al.¹²⁷127 Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A, et al. BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res. 2007;41(5):387-94. https://doi.org/10.1016/j.jpsychires.2006.01.014 https://doi.org/10.1016/j.jpsychires.200...	27 AD, 9 NPH, 29 healthy elderly controls. Cross-sectional.	AD and NPH	Significant decreases in BDNF serum levels in AD and NPH patients compared to healthy controls, reflecting a lack of trophic support and progressive neurodegeneration. BDNF serum levels did not correlate with MMSE, age, and CSF levels. No significant differences in BDNF levels in CSF in AD, NPH, and controls because of its low concentration. Further investigation is needed to explain the reasons for blood BDNF level reduction between AD and NPH patients.
Leyhe et al.¹²⁸128 Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C. Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2008;258(2):124-8. https://doi.org/10.1007/s00406-007-0764-9 https://doi.org/10.1007/s00406-007-0764-...	19 AD, 20 healthy elderly controls. Prospective cohort study.	AD	Serum BDNF levels were significantly decreased in the AD group before AChE-inhibitors treatment (10 mg Donepezil per day) and significantly increased after 15 months of treatment with no more significant difference from the control group. Down-regulation of BDNF begins with the first clinical symptoms and becomes persistent in the AD continuum, while up-regulation of BDNF happens along with the neuroprotective effect of AChE-inhibitor.
Angelucci et al.¹¹⁵115 Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, et al. Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res. 2010;7(1):15-20. https://doi.org/10.2174/156720510790274473 https://doi.org/10.2174/1567205107902744...	86 AD, 54 aMCI and MCI-MD, 27 healthy elderly controls. Cross-sectional.	aMCI, MCI-MD, mild AD, and moderate-sever AD	BDNF has a potential role as a biomarker during the AD course, shown by an upregulation of BDNF serum levels that significantly increased in MCI and AD compared to healthy groups. However, the BDNF levels among aMCI, MCI-MD, mild AD, and moderate-severe AD are insignificantly different. Upregulation of BDNF is an early compensatory against neurodegeneration.
Forlenza et al.¹¹⁶116 Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, et al. Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11(6):774-80. https://doi.org/10.3109/15622971003797241 https://doi.org/10.3109/1562297100379724...	30 AD, 71 MCI, 59 healthy elderly controls. Prospective cohort study.	AD and MCI	Decreased serum BDNF levels, along with a continuum of MCI to AD, indicate a reduced BDNF systemic availability that plays a role in the neurodegenerative process. The presence of the Met-BDNF allele and the APOE ε4 gene predict a worsened cognitive outcome in MCI patients.
O’Bryant et al.¹²⁹129 O’Bryant SE, Hobson VL, Hall JR, Barber RC, Zhang S, Johnson L, et al. Serum Brain-derived neurotrophic factor levels are specifically associated with memory performance among Alzheimer’s disease cases. Dement Geriatr Cogn Disord. 2011;31(1):31-6. https://doi.org/10.1159/000321980 https://doi.org/10.1159/000321980...	198 AD, 291 controls. Prospective cohort study.	AD	Serum BDNF levels increased in the AD group associated with lower neuropsychological function on visual and verbal memory. Still, they had no significant difference in BDNF levels compared to the control group.
Sonali et al.¹³⁰130 Sonali N, Tripathi M, Sagar R, Vivekanandhan S. Val66Met polymorphism and BDNF levels in Alzheimer’s disease patients in North Indian population. Int J Neurosci. 2013;123(6):409-16. https://doi.org/10.3109/00207454.2012.762515 https://doi.org/10.3109/00207454.2012.76...	63 AD, 15 aMCI, 63 healthy elderly controls. Cross-sectional.	AD and aMCI	Serum BDNF levels were insignificantly higher in the AD group than in the aMCI group controls. BDNF was insignificantly different in genotype and allele distribution between the three groups and did not significantly affect MMSE score in AD and aMCI. Further investigation is needed to examine the potential of BDNF as an AD biomarker.
Ventriglia et al.¹³¹131 Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D, Pasqualetti P, et al. Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013;2013:901082. https://doi.org/10.1155/2013/901082 https://doi.org/10.1155/2013/901082...	266 AD, 28 FTD, 40 LBD, 91 VaD, 30 PD, 169 healthy controls. Cohort retrospective and cross-sectional.	AD, FTD, LBD, VaD, and idiopathic PD.	BDNF levels decreased in several cognitive disorders as a non-specific marker for neurodegeneration. The use of psychotropic drugs during BDNF studies could create a confounding effect, therefore, needs to be controlled before BDNF analysis. BDNF can potentially be used as a new therapeutic target because it involves dementia and PD neuropathology.
Faria et al.¹³²132 Faria MC, Gonçalves GS, Rocha NP, Moraes EN, Bicalho MA, Cintra MTG, et al. Increased plasma levels of BDNF and inflammatory markers in Alzheimer’s disease. J Psychiatr Res. 2014;53:166-72. https://doi.org/10.1016/j.jpsychires.2014.01.019 https://doi.org/10.1016/j.jpsychires.201...	50 AD, 37 MC, 56 healthy elderly controls. Cross-sectional.	AD and MCI	AD patients showed a higher peripheral BDNF level reflecting a compensatory mechanism toward early neurodegeneration and related to immune cell activation (higher sTNFR1 and sICAM-1). Both peripheral BDNF and inflammatory markers are potentials to be an additional tool to differentiate cognitive impairment degrees.
Turana et al.⁶6 Turana Y, Ranakusuma TAS, Purba JS, Amir N, Ahmad SA, Machfoed MH, et al. Enhancing diagnostic accuracy of aMCI in the elderly: combination of olfactory test, pupillary response test, BDNF plasma level, and APOE genotype. Int J Alzheimers Dis. 2014;2014:912586. https://doi.org/10.1155/2014/912586 https://doi.org/10.1155/2014/912586...	51 aMCI, 58 healthy elderly controls. Cross-sectional.	aMCI	Low plasma BDNF levels and the presence of the APOE ε4 gene improve the diagnostic value of aMCI diagnostic tool combination using pupillary response and olfactory test.
Liu et al.¹³³133 Liu YH, Jiao SS, Wang YR, Bu XL, Yao XQ, Xiang Y, et al. Associations between ApoEε4 carrier status and serum BDNF levels--new insights into the molecular mechanism of ApoEε4 actions in Alzheimer’s disease. Mol Neurobiol. 2015;51(3):1271-7. https://doi.org/10.1007/s12035-014-8804-8 https://doi.org/10.1007/s12035-014-8804-...	110 AD, 120 healthy controls. Cross-sectional.	AD	Significantly lower serum BDNF levels in the AD group suggest an insufficient neurotrophic supply. BDNF levels were also significantly lower among all subjects in the AD group with APOE ε4 gene. BDNF possibly interacted with APOE ε4 and co-effects with MMSE scores. BDNF potential contributed to the molecular mechanism of the AD continuum.
Passaro et al.¹³⁴134 Passaro A, Nora ED, Morieri ML, Soavi C, Sanz JM, Zurlo A, et al. Brain-derived neurotrophic factor plasma levels: relationship with dementia and diabetes in the elderly population. J Gerontol A Biol Sci Med Sci. 2015;70(3):294-302. https://doi.org/10.1093/gerona/glu028 https://doi.org/10.1093/gerona/glu028...	44 late onset AD, 50 VaD, 23 CVD not dementia, 47 healthy controls. Cross-sectional.	AD, VaD, CVD not dementia	Plasma BDNF level in dementia (AD and VaD) groups affected by diabetes is the lowest among all subjects. BDNF levels affected by dementia synergically with diabetes status.
Ng et al.¹³⁵135 Ng TKS, Ho CSH, Tam WWS, Kua EH, Ho RCM. Decreased serum brain-derived neurotrophic factor (BDNF) levels in patients with Alzheimer’s disease (AD): a systematic review and meta-analysis. Int J Mol Sci. 2019;20(2):257. https://doi.org/10.3390/ijms20020257 https://doi.org/10.3390/ijms20020257...	2,067 AD and healthy control. Systematic review and meta-analysis.	AD	Serum BDNF levels were significantly lower in AD (excluding MCI) group than in controls with significant heterogenicity caused by age and MMSE scores as significant moderators during meta-regression analysis. Change in peripheral BDNF is only detected at the late stage of the AD continuum. Further investigation is needed, including molecular mechanisms, interventional trials, and BDNF potential use as an AD biomarker.
Mizoguchi et al.¹³⁶136 Mizoguchi Y, Yao H, Imamura Y, Hashimoto M, Monji A. Lower brain-derived neurotrophic factor levels are associated with age-related memory impairment in community-dwelling older adults: the Sefuri study. Sci Rep. 2020;10(1):16442. https://doi.org/10.1038/s41598-020-73576-1 https://doi.org/10.1038/s41598-020-73576...	256 elderlies with independent daily life without dementia. Cross-sectional observational study (2010 to 2016).	Memory impairment	Lower serum BDNF levels, older ages, lower physical activity, and hippocampal atrophy were associated with memory impairment independently. Impaired BDNF function (excluding proBDNF) combined with lower physical activity and hippocampal atrophy is associated with age-related memory impairment; therefore, BDNF is potentially used as a therapeutic target to prevent dementia.
Mori et al.¹³⁷137 Mori Y, Tsuji M, Oguchi T, Kasuga K, Kimura A, Futamura A, et al. Serum BDNF as a potential biomarker of Alzheimer’s disease: verification through assessment of serum, cerebrospinal fluid, and medial temporal lobe atrophy. Front Neurol. 2021;12:653267. https://doi.org/10.3389/fneur.2021.653267 https://doi.org/10.3389/fneur.2021.65326...	23 AD, 22 MCI, 21 healthy controls. Cross sectional.	AD and MCI	MCI group had significantly lower serum BDNF levels compared to the control group. AD group had a downward trend of serum BDNF levels than control group, but was not statistically significant. BDNF levels have a positive correlation with Aβ42 levels in CSF. The decreased serum BDNF levels could potentially be used as an AD early detection and progression biomarker.
Ng et al.¹³⁸138 Ng TKS, Coughlan CM, Heyn PC, Tagawa A, Carollo J, Kua EH, et al. Increased plasma brain-derived neurotrophic factor (BDNF) as a biomarker for differentiating mild cognitive impairment from cognitive healthy: a case-control study. Alzheimers Dement. 2021;17(S5):e058648. https://doi.org/10.1002/alz.058648 https://doi.org/10.1002/alz.058648...	40 aMCI and non-aMCI, 56 healthy controls. Case-control.	aMCI, and non-aMCI	Plasma BDNF levels significantly increased in all MCI subjects with good discriminative accuracy as an early compensatory mechanism in preclinical dementia. BDNF is also correlated with neurotrophic and inflammation because it positively correlates with plasma high-sensitivity C-reactive protein.
Perkovic et al.¹³⁹139 Perkovic MN, Borovecki F, Filipcic I, Vuic B, Milos T, Erjavec GN, et al. Relationship between brain-derived neurotrophic factor and cognitive decline in patients with mild cognitive impairment and dementia. Biomolecules. 2023;13(3):570. https://doi.org/10.3390/biom13030570 https://doi.org/10.3390/biom13030570...	295 AD, 209 MCI.	AD and MCI	The increase in plasma BDNF levels in AD patients more significantly than in the MCI group might be due to counteracting mechanisms in the early-middle stage of neurodegeneration.

Clinical trial official title, NCT ID and access	Participant number and interventions	Diseases and outcome measures	Publication outcome - key findings
“A Single Center, Multi-site, Randomized, Double-blind, Placebo-controlled Trial of Resveratrol with Glucose and Malate (RGM) to Slow the Progression of Alzheimer’s Disease”	27 participants.	AD	Zhu et al.¹⁴⁰140 Zhu CW, Grossman H, Neugroschl J, Parker S, Burden A, Luo X, et al. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: a pilot study. Alzheimers Dement (NY). 2018;4:609-16. https://doi.org/10.1016/j.trci.2018.09.009 https://doi.org/10.1016/j.trci.2018.09.0... Low-dose of oral resveratrol at 12 months showed less deterioration of neurocognitive scores in the AD group than controls. It is safe and well tolerated, but further larger studies are needed to determine its benefit in interpreting clinical outcomes.
	Dietary Supplement: Resveratrol with Glucose, and Malate (delivered in grape juice)	AD
		Primary: ADAScog
NCT00678431 (https://clinicaltrials.gov/show/NCT00678431) “A Randomized, Double-Blind, Placebo-Controlled Trial of Vitamin E and Donepezil HCL (Aricept) to Delay Clinical Progression from Mild Cognitive Impairment (MCI) to Alzheimer’s Disease (AD)”		Secondary: CGIC
	Dietary Supplement:Liquid placebo	Secondary: CGIC
	720 participants.	AD	Petersen et al.¹⁴¹141 Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352(23):2379-88. https://doi.org/10.1056/NEJMoa050151. https://doi.org/10.1056/NEJMoa050151...
	720 participants.	Primary:NINCDS-ADRDA Alzheimer’s Criteria	No significant difference in probable progression to AD in the group given with vitamin E than controls. No benefit of vitamin E in MCI patients.
	Drug: Vitamin E Drug: Donepezil	Primary:NINCDS-ADRDA Alzheimer’s Criteria
NCT00000173 (https://clinicaltrials.gov/show/NCT00000173)	Drug: Vitamin E Drug: Donepezil	Secondary: CDR
“Sunphenon EGCg (Epigallocatechin-Gallate) in the Early Stage of Alzheimer’s Disease”	21 participants.	AD	No results published/posted
	21 participants.	Primary:ADAS-COG
	Drug:Epigallocatechin-Gallatea Drug: Placebo	Secondary: Safety and tolerability of the verum; MMSE; Time to hospitalization and Time to death related to AD; Brain atrophy assessed by brain MRI; Baseline-ADAS-COG and Baseline-MMSE as covariates; CIBIC+ and WHOQOL-Bref; Trail Making Test and MVGT
NCT00951834 (https://clinicaltrials.gov/show/NCT00951834)	Drug:Epigallocatechin-Gallatea Drug: Placebo
“Study of Melatonin: Sleep Problems in Alzheimer’s Disease”	157 participants	AD and Dyssomnias.	Singer et al.¹⁴²142 Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep. 2003;26(7):893-901. https://doi.org/10.1093/sleep/26.7.893 https://doi.org/10.1093/sleep/26.7.893...
		Primary: Change of nocturnal sleep time from baseline to the end of treatment phase
			Melatonin is not effective a soporific agent in AD group based on actigraphy showed by no statistically significant objective sleep measures difference in intervention and control group.
NCT00000171(https://clinicaltrials.gov/show/NCT00000171)	Drug: MelatoninDrug: Placebo	Secondary: Time awake after sleep onset, sleep latency, sleep efficiency, daytime agitation, changes in cognition, relative effectiveness of high and low dose melatonin
“A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD)”	613 participants.	AD	Dysken et al.¹⁴³143 Dysken MW, Guarino PD, Vertrees JE, Asthana S, Sano M, Llorente M, et al. Vitamin E and memantine in Alzheimer’s disease: clinical trial methods and baseline data. Alzheimers Dement. 2014;10(1):36-44. https://doi.org/10.1016/j.jalz.2013.01.014 https://doi.org/10.1016/j.jalz.2013.01.0... ,¹⁴⁴144 Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44. https://doi.org/10.1001/jama.2013.282834 https://doi.org/10.1001/jama.2013.282834...
	613 participants.	AD	Alpha-tocopherol (Vitamin E) is beneficial in mild and moderate AD by slowing a functional decline and lowering caregiver burden. The differences in the group taking memantine and memantine plus alpha-tocopherol were insignificant.
	Drug: dl-alpha-tocopherol (Vitamin E)Drug: Memantine (Namenda (R))	Primary: ADCS/ADL
NCT00235716(https://clinicaltrials.gov/show/NCT00235716)		Primary: ADCS/ADL
NCT00235716(https://clinicaltrials.gov/show/NCT00235716)		Secondary: MMSE, ADAS-COG, NPI, CAS, Dependence Scale
“Multicenter Vitamin E Trial in Aging Persons with Down Syndrome”	350 participants.	AD and down-syndrome.
NCT01594346 (https://clinicaltrials.gov/show/NCT01594346)	Drug: Alpha-tocopherol(Vitamin E)Drug: Sugar pill	AD and down-syndrome.	No results published/posted
NCT01594346 (https://clinicaltrials.gov/show/NCT01594346)	Drug: Alpha-tocopherol(Vitamin E)Drug: Sugar pill	Primary: BPT	No results published/posted

[1] Correspondence: Yuda Turana; Email: yuda.turana@atmajaya.ac.id.

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Interação do fator neurotrófico encefálico com o estresse oxidativo: abordagem neuropatológica a um potencial biomarcador da doença de Alzheimer

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