Journal of Alzheimers & Neurodegenerative Diseases Category: Clinical Type: Research Article

Progress in Facilitating Therapy for Alzheimer's Disease : Non-Invasive Treatment

YUE Xiang Pei1, CHENG Xiang1, ZHU Ling Ling2 and31*
1 Academy of military medical sciences, Institute of Military Cognition and Brain Sciences, Beijing, 100850, China

*Corresponding Author(s):
ZHU Ling Ling2,3
Academy Of Military Medical Sciences, Institute Of Military Cognition And Brain Sciences, Beijing, 100850, China
Tel:+86-10-66931315,
Email:linglingzhuamms@126.com

Received Date: Feb 21, 2020
Accepted Date: Mar 09, 2020
Published Date: Mar 16, 2020

Abstract

With the aging of the global population, the number of Alzheimer's disease has increased rapidly. Alzheimer's disease has become one of the major diseases affecting human health, and no drugs can reverse its progression. Because of its unclear etiology and complex pathological mechanism, the newly developed single target drugs do not work well in clinical trials. Recently, more and more studies have shown that some non-invasive stimuli, such as light therapy, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, physical activity, intermittent hypoxic training and others can improve the cognitive behaviour and pathological changes of Alzheimer's disease. Here, we review the research progress of these non-invasive therapies in the treatment of Alzheimer's disease and discusses their potential application.

Keywords

Alzheimer’s disease; Light therapy; Repetitive transcranial magnetic stimulation; Transcranial direct current stimulation; Physical activity; Intermittent hypoxic training.

INTRODUCTION

Dementia and severe cognitive impairment are very closely linked to ageing [1,2]. With the aging of the global population, the population of Alzheimer's disease (AD) is expected to fourfold by 2050 [3]. The main neuropathological characteristics of the AD brain are extracellular neurotic plaques which is Aβ deposition and intracellular neurofibrillary tangles which is the hyper phosphorylated accumulation [4]. These pathological changes are often accompanied by reactive microglial proliferation and loss of neurons and synapses [3]. Cognitive decline, emotional, behavioural and sleep disorders, as well as restrictions on activities of daily living, often increase the burden on AD patients and their caregivers [5]. Efforts need to be made to improve the national dementia care system, strengthen the skills and knowledge training of medical personnel, and actively carry out global cooperation to prevent and treat the disease [6-9]. Existing medical treatment for AD have limited effectiveness, expensive, and sometimes causing serious side effects. Therefore, alternative or complementary adjuvant treatment strategies, such as light therapy, transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), physical activity and intermittent hypoxic training (IHT) etc, have gained more and more attention. As a new noninvasive brain stimulation method, neuromodulation technology has attracted more and more attention in the treatment of AD cognitive impairment [10].

Light therapy

Light therapy is a kind of non-invasive non pharmacological treatment method, with different wavelengths, intensities, durations and different region in application. Many researchers find that low-power laser photobiological could attenuate Aβ-induced cell apoptosis [11,12]. It is found that light therapy can increase ATP and mitochondrial membrane potential, reduce intracellular calcium concentration and lighten oxidative stress. This may be the reason why phototherapy plays a beneficial role in central nervous system diseases [13]. Let's take a look at its application in AD at (Table1).

Research subject/Author/year

Method

Human subject research

Nonhuman subject research

PC12, SH-SY5Y, HEK 293T cell[11]

Low-power laser irradiation

/

Aβ (25-35)-induced apoptosis (-)

PC12?HEK 293 T cell [12]

Low-power laser irradiation

/

Aβ (25-35)-induced apoptosis (-)

Dementia patients [14]

bright light, 1000lux

MMSE?+?, CSDD (+)

/

Demented patients [15]

bright light, 3000 lux

MMSE?+?

/

Demented patients [16]

bright light

DSAOA?+?, CSDD (+)

/

AD patients [18]

bright light, 2500 lux

Sleep?+?, Circadian rhythms?+?

/

AD patients [20]

bright light, 5000/2500 lux

NPI-NH?+?

/

Dementia patients [22]

bright light, 10000 lux

CGIC?+?

/

AD patients[23]

bright light, 5000-8000 lux

CMAI?+?, BEHAVE-AD?+?

/

Dementia mouse model[26]

λ=630 nm

/

Cognitive (+)

AD mouse model [27]

λ=808 ± 10 nm

/

Aβ levels (-)

AD mouse model [28]

λ=1072 nm

/

Aβ levels (-)

AD mouse model [29]

λ=670 nm

/

Aβ levels (-)

AD mouse model [30]

Low-power laser irradiation

/

Aβ levels (-), Cognitive (+)

AD patients [31]

λ=810 nm

ADAS-cog?+?, MMSE?+?

/

AD mouse model [32]

40 Hz light flicker

/

Aβ levels (-)

AD mouse model [32]

40 Hz light flicker

/

Aβ levels (-)

AD mouse model [34]

40 Hz auditory and visual GENUS

/

Aβ levels (-), Cognitive (+)

Table 1: Research summery of light therapy for AD.

Bright light therapy

Bright light therapy has a certain effect in improving cognitive and noncognitive symptoms of dementia [14]. Specifically, firstly, there is a statistically significant increase in MMSE total scores after bright light therapy [15]; Secondly, it causes an effective intervention for depression in both mild/moderate and severe dementia [16]. Depression is widespread in the elderly and may be an early manifestation of AD [17]; thirdly, the application of bright light therapy consolidates sleep and strengthens diurnal rhythms in dementia [18-20]. It is worth mentioned that, the latest research shows that sleep maybe a biomarker of tau and Aβ burden in human brain [21]. Last but not least, even in severe dementia, bright light can improve behavioural symptoms and activity rhythm disturbances [22,23]. However, the biological mechanism by bright light therapy remains to be elucidated.

Different wavelengths

According to the reports, red to infrared light therapy (λ=600-1070 nm), and particularly light in the near infrared wavelength range, is becoming a relative safe and effective treatment therapy, which is capable of preventing neuronal death [24]. Also, low-power laser irradiation (λ=632 nm) has been applied to the spinal cord, which helps recover the relevant insured peripheral nerve [25]. These suggests that light with different wavelengths may play a useful role in AD. Light-emitting diode (λ=630nm) reduces brain H2O2 levels and reverses age-related memory disorders in SAMP8 (senescence-accelerated prone 8 mouse, a model of age-related dementia) [26]. There are many statements mean that non-invasive light therapy (λ=670 nm, 808 nm, 1072 nm) reduces AD-related pathologies in the brain of animal model, near infrared light treatment is related to the reduction of hyperphosphorylated tau, neurofibrillary tangles, the size and number of amyloid-β plaques and the expression of inflammatory markers[27-30]. In mild to moderately severe dementia, research workers apply light-emitting diode devices combining transcranial plus intranasal photobiological regulation (810 nm) to treat the cortical nodes of the DMN (bilateral mesial prefrontal cortex, precuneus/posterior cingulate cortex, angular gyrus, and hippocampus), find that it improves cognitive ability significantly [31].

Specific frequency

The Tsai team recently reported that non-invasive scintillation light (gamma entrainment using sensory stimulus or GENUS) in AD model mice can induce gamma oscillations, thus causing pathological changes in the visual cortex of mice[32]namely, non-invasive 40 Hz light-flicker treatment could reduce the levels of Aβ1-40 and Aβ1-42 in the visual cortex and reduced the plaque load in aged, depositing mice[33]. Not long ago, they designed auditory tone stimulation to induce gamma frequency in the brain, thus regulating nerve activity, the results shows that 7 days auditory stimulation improved the memory ability and reduced amyloid plaque in AC and hippocampus of 5XFAD mice [34].

NEUROPHYSIOLOGICAL TECHNIQUES: TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) AND REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (RTMS)

Not only light therapy, recently new neurophysiological tools, such as rTMS and tDCS, which apply noninvasive transcranial electrical or magnetic stimulation to regulate neuronal activity, has been introduced into basic and clinical research of brain science [35]. Let's take a look at their application in AD at (Table 2).

Research subject/Author/Year

Method

Human subject research

Nonhuman subject research

AD patients[41]

tDCS, 2 mA

MMMSE?+??MoCA?+?

/

AD patients [42]

tDCS, 2 mA

MMSE?+??Boston Naming Test?+?

/

AD patients [43]

tDCS, 2 mA

visual recognition memory?+?

/

AD patients [44]

tDCS, 2 mA

visual recognition memory?+?,

persists for at least 4 weeks

/

AD patients[45]

tDCS, 1.5 mA

word recognition memory task?+?

/

AD patients [47]

rTMS, 20 Hz

MMSE?+?, IADL?+?, GDS?+?

/

AD patients [48]

rTMS, 20 Hz

sentence comprehension?+?

/

AD patients [49]

rTMS, 20 Hz

naming performance?+?

/

AD patients[50]

rTMS, 10 Hz

MMSE?+?

/

MCI+AD patients [51]

rTMS, 10 Hz

TMT?+?

/

AD patients [52]

rTMS, 20 Hz

episodic memory?+?

/

AD patients [53]

rTMS, 5 Hz

MMSE?+?, ADAS-cog?+?, NPI?+?

/

AD rat model [54]

rTMS, 1 Hz

/

rescued deficits in LTP and spatial memory

AD mouse model [55]

rTMS, 1 Hz

/

reversed the impairment of spatial learning and memory

AD rat model [56]

rTMS, 5 Hz

/

Enhance BDNF-TrkBsignaling in both brain and lymphocyte

AD patients [59]

rTMS-COG?10 Hz

ADAS-cog?+??CGIC?+?

/

AD patients [60]

rTMS-COG?10 Hz

ADAS-cog?+??CGIC?+?, NPI?+?

/

AD patients[61]

rTMS-COG?10 Hz

ADAS-cog?+?, CGIC?+?, MMSE?+?

/

AD patients [62]

rTMS-COG?10 Hz

ADAS-cog?+?, MMSE?+?, persists for at least 9 months

/

AD patients [63]

rTMS-COG?10 Hz

ADAS-cog?+?

/

Table 2: Research summery of neurophysiological techniques for AD.

MMSE-Mini Mental State Examination; CGIC- Clinical Global Impression of Change; CMAI- Cohen-Mansfield Agitation Inventory; BEHAVE-AD- Behavior Pathology In Alzheimer's Disease Rating Scale; CSDD- Cornell Scale for Depression in Dementia; ADAS-Cog- Alzheimer’s Disease Assessment Scale-Cognitive; NPI-NH- Neuropsychiatric Inventory , Nursing Home version; DSAOA-Depressive Symptom Assessment for Older Adults; GENUS- Gamma Entrainment Using Sensory Stimulus; IADL- Instrumental Daily Living Activity; GDS- Geriatric Depression Scale;MCI- Mild Cognitive Impairment; TMT- Trail Making Test; NPI-Neuropsychiatric Inventory; MMMSE- Modified Mini Mental State Examination (MMMSE); MoCA- Montreal Cognitive Scale.

 

tDCS

Transcranial electrical stimulation with weak electric current may be a promising approach to modulate brain excitability with non-invasive, painless, reversible and regional advantage [36-38]. Its function can be realized by changing the current intensity and duration, tDCS is widely used in human neuroscientific and clinical research at present [39]. In the humans, tDCS is able to lead sustained cortical excitability [40]cognitive improvements after 10 sessions of anodal tDCS in patients with AD patients [41]. Daily tDCS over the dorsolateral prefrontal cortex for 6 months may improve or stable cognition and regional cerebral metabolic rate for glucose in AD patients [42]. After AD patients received tDCS treatment, they perform better on visual recognition memory tests [43,44]and word recognition memory [45] significantly improved.

rTMS

TMS is a non-invasive technique that can produce current induced cortical excitability. It is considered that the application of 10, 15 or 20 Hz rTMS over the left dorsolateral prefrontal cortex, in the range of 10-15 successive sessions and 80-110% of individual motor threshold, is most probably to get rise to significant cognitive amelioration[46,47] and beneficial effects sentence comprehension[48]. There is a good deal of evidence that TMS has been considered as a possible treatment method for the cognitive impairment in AD patients [49-52]. Not only that, After 3 weeks of treatment, the cognitive function, behaviour and function of AD patients can be improved, and the effect can be maintained for more than 4 weeks [53].

Studies have shown that noninvasiverTMS treatment may effectively ameliorates cognitive and synaptic functions in AD mice model by reducing the Aβ neuropathology [54,55]. It has been reported that rTMS to cortex promotes BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes in rats [56]and it also regulates the glutamate and gamma-aminobutyric acid systems [57].

Research shows that cognitive training (COG) may effectively improve the cognitive functions of AD patients, mainly including learning, memory and daily life capability [58]. In general, rTMS-COG seems to be a promising effective and safe treatment for AD [59-63].

PHYSICAL ACTIVITY AND INTERMITTENT HYPOXIC TRAINING

One of the most effective strategies to maintain physical and mental health is physical activity, which can promote brain plasticity, improve cognitive ability, and reduce the risk of cognitive decline [64-66]. Regular aerobic exercise can slow down the progress of AD in high risk population. In a middle-aged, at-risk cohort, a physically active lifestyle can decrease the key biomarkers of AD pathophysiology [67]. The researchers argue that physical activity and cognitive training may prevent recognition memory defects related to Aβ neurotoxicity [68,69]. Treadmill exercise ameliorates short-term memory by boosting neurogenesis in Aβ-induced AD rats model [70].

Oxygen is essential for maintaining the normal function of almost all organs, especially for the brain, which is one of the most oxygen consuming organs in the body. Exercise includes aerobic exercise and anaerobic exercise, mainly through the regulation of body metabolism, to stimulate the potential in the body. Moderate or intermittent hypoxic training is also an important means of against hypoxic injury intervention, which has been applied to improve endurance of athletes. In the course of Aβ-induced pathology metabolic dysfunction is an early and causative event [71]. It has been reported that adaptation to cyclic hypoxia can effectively prevent oxidative and nitrous stress, prevent neurodegeneration and protect cognitive function in experimental AD rats.[72,73] and they hypothesized that adaptation to induced hypoxia may prevent dementia, the protective mechanisms may be due to reducing oxidative stress and increasing the density of cerebral vascular network [74]. Our team found that moderate hypoxia (22.8-76 mmHg) can promote the proliferation of neural stem cells and enhance the differentiation of neural stem cells into the TH-positive neurons [75]. There is also epidemiological evidence for such effects, that is altitude of residence may impact the risk for dying of Alzheimer dementia [76]. There is a growing number of evidence that intermittent hypoxic training (IHT) can mobilize human potential and enhance cerebrovascular function, which is beneficial to hypertension, arrhythmia and mental stress [77].

OTHER WAYS

To prevent and cure AD, in addition to the above-mentioned treatment methods, it also involves nutrition, music, social activities, etc. People who actively participate in social activities and play games have a relatively low risk of mild cognitive impairment [78]. Using a computer, engaging in a higher number of mentally stimulating activities, is associated with a decreased risk of mild cognitive impairment among community-dwelling older persons[79]. The risk of dementia is associated with lifestyle, and good lifestyle implies a lower risk of dementia [80]. More than this, Nutrition can directly modulate susceptibility to AD [81]. Reduce trans fatty acids may contribute to the primary prevention of dementia [82]. Dietary salt promotes tau phosphorylation, which leads to cognitive impairment, a salt-rich diet can make nitric oxide decrease in brain endothelial cells and cerebral hypoperfusion reduction, resulting in cognitive impairment [83]. Modified Mediterranean-ketogenic diet modulates intestinal microorganisms and short-chain fatty acids in association with AD markers in patients with mild cognitive impairment [84]. Music intervention and chair-based exercise may improve significantly in quality of life in AD [85,86].

CONCLUSION

So far, no breakthrough has been made in drug development for AD, the progress of novel non-invasive brain stimulation methods has shown promise as a non-pharmacological treatment. Walking, light and their combination are effective therapies to improve sleep quality of AD patients [87]. TMS and tDCS can regulate nerve excitability in a non-invasive, painless and reversible way, making them potential valuable tools. Recently, a clinical trial of transcranial electromagnetic therapy for AD shows that it can enhance cognition and brain connection [88]. Nutrition may develop into one of the ways to prevent or even treat AD, especially if combined with other treatments, such as antidepressant intervention, brain exercise, physical exercise, etc[89]. Mediterranean diet and physical activity both can reduce the risk of AD [90]. As for IHT, it has also been reported that it has beneficial effects not only on AD but also on other neuropathy, including circulatory disorders, ischemic stroke. Therefore, it is necessary to further study the potential advantages of IHT in AD and its specific mechanism.

ACKNOWLEDGEMENT

Funding: This work was supported by the grants from Beijing Science and technology Commission (No.Z161100000216134).

REFERENCES

  1. BrayneC, Gao L, Dewey M, Matthews FE, Medical Research Council Cognitive Function and Ageing Study Investigators (2006) Dementia before death in ageing societies--the promise of prevention and the reality. Plos Med 3: e397.
  2. Larson EB, Langa KM (2008) The rising tide of dementia worldwide. Lancet 372: 430-432.
  3. Reitz C, Mayeux R (2014) Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. BiochemPharmacol 88: 640-651.
  4. Long JM, Holtzman DM (2019) Alzheimer Disease: An update on pathobiology and treatment strategies. Cell 179: 312-339.
  5. Wimo A, JönssonL, Bond J, Prince M, Winblad B, et al. (2013) The worldwide economic impact of dementia 2010. Alzheimers Dement 9: 1-11.e3.
  6. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, et al. (2013) The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement 9: 63-75.e2.
  7. Alzheimer's Association (2016) 2016 Alzheimer's disease facts and figures. Alzheimers Dement 12: 459-509.
  8. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, et al. (2017) Dementia prevention, intervention, and care. Lancet 390: 2673-2734.
  9. Jia L, Quan M, Fu Y, Zhao T, Li Y, et al. (2019) Dementia in China: Epidemiology, clinical management, and research advances. Lancet Neurol 19: 81-92.
  10. Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, et al. (2012) Effect of transcranial brain stimulation for the treatment of Alzheimer disease: A review. Int J Alzheimers Dis 2012: 687909.
  11. Liang J, Liu L, Xing D (2012) Photobiomodulation by low-power laser irradiation attenuates Aβ-induced cell apoptosis through the Akt/GSK3β/β-catenin pathway. Free RadicBiolMed 53: 1459-1467.
  12. Zhang H, Wu S, Xing D (2012) Inhibition of Aβ(25-35)-induced cell apoptosis by low-power-laser-irradiation (LPLI) through promoting Akt-dependent YAP cytoplasmic translocation. Cell Signal 24: 224-232.
  13. Huang YY, Nagata K, Tedford CE, Hamblin MR (2014) Low-level laser therapy (810 nm) protects primary cortical neurons against excitotoxicity in vitro. J Biophotonics 7: 656-664.
  14. der Lek RF R, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, et al. (2008) Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: A randomized controlled trial. JAMA 299: 2642-2655.
  15. Graf A, Wallner C, Schubert V, Willeit M, Wlk W, et al. (2001) The effects of light therapy on mini-mental state examination scores in demented patients. Biol Psychiatry 50: 725-727.
  16. Onega LL, Pierce TW, Epperly L (2018) Bright Light Therapy to Treat Depression in Individuals with Mild/Moderate or Severe Dementia. Issues Ment Health Nurs 39: 370-373.
  17. Gatchel JR, Rabin JS, Buckley RF, Locascio JJ, Quiroz YT, et al. (2019) Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults. JAMA NetwOpen 2: e198964.
  18. Ancoli-Israel S, Gehrman P, Martin JL, Shochat T, Marler M, et al. (2002) Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer's disease patients. Behav Sleep Med 1: 22-36.
  19. vanMaanen A, Meijer AM, van der HeijdenKB, Oort FJ (2016) The effects of light therapy on sleep problems: A systematic review and meta-analysis. Sleep Med Rev 29: 52-62.
  20. Sekiguchi H, Iritani S, Fujita K (2017) Bright light therapy for sleep disturbance in dementia is most effective for mild to moderate Alzheimer's type dementia: A case series. Psychogeriatrics 17: 275-281.
  21. Winer JR, Mander BA, Helfrich RF, Maass A, Harrison TM, et al. (2019) Sleep as a Potential Biomarker of Tau and β-Amyloid Burden in the Human Brain. J Neurosci 39: 6315-6324.
  22. Haffmans PM, Sival RC, Lucius SA, Cats Q, van Gelder L (2001) Bright light therapy and melatonin in motor restless behaviour in dementia: a placebo-controlled study. Int J Geriatr Psychiatry 16: 106-110.
  23. Skjerve A, Holsten F, Aarsland D, Bjorvatn B, Nygaard HA, et al. (2004) Improvement in behavioral symptoms and advance of activity acrophase after short-term bright light treatment in severe dementia. Psychiatry ClinNeurosci 58: 343-347.
  24. Johnstone DM, Moro C, Stone J, Benabid AL, Mitrofanis J (2016) Turning On Lights to Stop Neurodegeneration: The Potential of Near Infrared Light Therapy in Alzheimer's and Parkinson's Disease. Front Neurosci 9: 500.
  25. Rochkind S, Nissan M, Alon M, Shamir M, Salame K (2001) Effects of laser irradiation on the spinal cord for the regeneration of crushed peripheral nerve in rats. Lasers SurgMed 28: 216-219.
  26. Zhang J, Yue X, Luo H, Jiang W, Mei Y, et al. (2019) Illumination with 630 nm Red Light Reduces Oxidative Stress and Restores Memory by Photo-Activating Catalase and Formaldehyde Dehydrogenase in SAMP8 Mice. Antioxid Redox Signal 30: 1432-1449.
  27. De Taboada L, Yu J, El-Amouri S, Gattoni-Celli S, Richieri S, et al. (2011) Transcranial laser therapy attenuates amyloid-β peptide neuropathology in amyloid-β protein precursor transgenic mice. J Alzheimers Dis 23: 521-535.
  28. Grillo SL, Duggett NA, Ennaceur A, Chazot PL (2013) Non-invasive infra-red therapy (1072 nm) reduces β-amyloid protein levels in the brain of an Alzheimer's disease mouse model, TASTPM. J PhotochemPhotobiol B 123: 13-22.
  29. Purushothuman S, Johnstone DM, Nandasena C, Mitrofanis J, Stone J (2014) Photobiomodulation with near infrared light mitigates Alzheimer's disease-related pathology in cerebral cortex-evidence from two transgenic mouse models. Alzheimers Res Ther 6: 2.
  30. Farfara D, Tuby H, Trudler D, Doron-Mandel E, Maltz L, et al. (2015) Low-level laser therapy ameliorates disease progression in a mouse model of Alzheimer's disease. J MolNeurosci 55: 430-436.
  31. Saltmarche AE, Naeser MA, Ho KF, Hamblin MR, Lim L (2017) Significant Improvement in Cognition in Mild to Moderately Severe Dementia Cases Treated with Transcranial Plus Intranasal Photobiomodulation: Case Series Report. Photomed Laser Surg 35: 432-441.
  32. Singer AC, Martorell AJ, Douglas JM, Abdurrob F, Attokaren MK, et al. (2018) Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc 13: 1850-1868.
  33. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, et al. (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540: 230-235.
  34. Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, et al. (2019) Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell 177: 256-271.e22.
  35. Pilato F, Profice P, Ranieri F, Capone F, Di IR, et al. (2012) Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques. MolNeurobiol 46: 563-571.
  36. Nitsche MA, Paulus W (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. JPhysiol 527: 633-639.
  37. Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, et al. (2008) Transcranial direct current stimulation: State of the art 2008. Brain Stimul 1: 206-223.
  38. Kuo MF, Paulus W, Nitsche MA (2014) Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 85: 948-60.
  39. Flöel A (2014) tDCS-enhanced motor and cognitive function in neurological diseases. Neuroimage 85: 934-947.
  40. Nitsche MA, Paulus W (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57: 1899-901.
  41. Khedr EM, Salama RH, Abdel HM, Abo EN, Seif P (2019) Therapeutic Role of Transcranial Direct Current Stimulation in Alzheimer Disease Patients: Double-Blind, Placebo-Controlled Clinical Trial. Neurorehabil Neural Repair 33: 384-394.
  42. Im JJ, Jeong H, Bikson M, Woods AJ, Unal G, et al. (2019) Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer's disease. Brain Stimul 12: 1222-1228.
  43. Boggio PS, Khoury LP, Martins DC, Martins OE, de Macedo EC, et al. (2009) Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J NeurolNeurosurg Psychiatry 80: 444-447.
  44. Boggio PS, Ferrucci R, Mameli F, Martins D, Martins O, et al. (2012) Prolonged visual memory enhancement after direct current stimulation in Alzheimer's disease. Brain Stimul 5: 223-230.
  45. Ferrucci R, Mameli F, Guidi I, Mrakic-Sposta S, Vergari M, et al. (2008) Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology 71: 493-498.
  46. Guse B, Falkai P, Wobrock T (2010) Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review. J Neural Transm(Vienna) 117: 105-122.
  47. Ahmed MA, Darwish ES, Khedr EM, El SYM, Ali AM (2012) Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia. J Neurol 259: 83-92.
  48. Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, et al. (2011) Improved language performance in Alzheimer disease following brain stimulation. J NeurolNeurosurg Psychiatry 82: 794-797.
  49. Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C (2008) Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. EurJ Neurol 15: 1286-1292.
  50. Haffen E, Chopard G, Pretalli JB, Magnin E, Nicolier M, et al. (2012) A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease. Brain Stimul 5: 264-266.
  51. Eliasova I, Anderkova L, Marecek R, Rektorova I (2014) Non-invasive brain stimulation of the right inferior frontal gyrus may improve attention in early Alzheimer's disease: a pilot study. J NeurolSci 346: 318-322.
  52. Koch G, Bonnì S, Pellicciari MC, Casula EP, Mancini M, et al. (2018) Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage169: 302-311.
  53. Alcalá-Lozano R, Morelos-Santana E, Cortés-Sotres JF, Garza-Villarreal EA, Sosa-Ortiz AL, et al. (2018) Similar clinical improvement and maintenance after rTMS at 5 Hz using a simple vs. complex protocol in Alzheimer's disease. Brain Stimul 11: 625-627.
  54. Tan T, Xie J, Liu T, Chen X, Zheng X, et al. (2013) Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) reverses Aβ(1-42)-mediated memory deficits in rats. ExpGerontol 48: 786-794.
  55. Huang Z, Tan T, Du Y, Chen L, Fu M, et al. (2017) Low-Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Function and Synaptic Plasticity in APP23/PS45 Mouse Model of Alzheimer's Disease. Front Aging Neurosci 9: 292.
  56. Wang HY, Crupi D, Liu J, Stucky A, Cruciata G, et al. (2011) Repetitive transcranial magnetic stimulation enhances BDNF-TrkBsignaling in both brain and lymphocyte. J Neurosci 31: 11044-11054.
  57. Yue L, Xiao-lin H, Tao S (2009) The effects of chronic repetitive transcranial magnetic stimulation on glutamate and gamma-aminobutyric acid in rat brain. Brain Res 1260: 94-99.
  58. Sitzer DI, Twamley EW, Jeste DV (2006) Cognitive training in Alzheimer's disease: A meta-analysis of the literature. ActaPsychiatrScand 114: 75-90.
  59. Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, et al. (2011) Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: A proof of concept study. J Neural Transm(Vienna) 118: 463-471.
  60. Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, et al (2013). Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: a randomized, double-blind study. J Neural Transm (Vienna) 120: 813-819.
  61. Lee J, Choi BH, Oh E, Sohn EH, Lee AY (2016) Treatment of Alzheimer's Disease with Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study. J ClinNeurol 12: 57-64.
  62. Rabey JM, Dobronevsky E (2016) Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: clinical experience. J Neural Transm (Vienna) 123: 1449-1455.
  63. Nguyen JP, Suarez A, Kemoun G, Meignier M, Le Saout E, et al (2017). Repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease. NeurophysiolClin 47: 47-53.
  64. Bernardo TC, Marques-Aleixo I, Beleza J, Oliveira PJ, AscensãoA, et al. (2016) Physical Exercise and Brain Mitochondrial Fitness: The Possible Role Against Alzheimer's Disease. Brain Pathol 26: 648-663.
  65. Veronese N, Solmi M, Basso C, Smith L, Soysal P (2010) Role of physical activity in ameliorating neuropsychiatric symptoms in Alzheimer disease: A narrative review. Int J Geriatr Psychiatry 34: 1316-1325.
  66. Najar J, Östling S, Gudmundsson P, Sundh V, Johansson L, et al. (2019) Cognitive and physical activity and dementia: A 44-year longitudinal population study of women. Neurology 92: 1322-1330.
  67. Okonkwo OC, Schultz SA, Oh JM, Larson J, Edwards D, et al. (2014) Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology 83: 1753-1760.
  68. Rabin JS, Klein H, Kirn DR, Schultz AP, Yang HS, et al. (2019) Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults. JAMA Neurol76:1203-1210.
  69. Rossi DL, Garcia A, Alves N, Ventura DD, de Souza MA, et al. (2019) Physical and cognitive training are able to prevent recognition memory deficits related to amyloid beta neurotoxicity. Behav Brain Res 365: 190-197.
  70. Kim BK, Shin MS, Kim CJ, Baek SB, Ko YC, et al. (2014) Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease rats. J ExercRehabil 10: 2-8.
  71. Teo E, Ravi S, Barardo D, Kim HS, Fong S, et al. (2019) Metabolic stress is a primary pathogenic event in transgenic Caenorhabditiselegans expressing pan-neuronal human amyloid beta. Elife 8.
  72. Manukhina EB, Goriacheva AV, Barskov IV, Viktorov IV, Guseva AA, et al (2009). Prevention of the brain neurodegeneration in rats with experimental Alzheimer's disease by adaptation to hypoxia. Ross FiziolZhIm I M Sechenova 95: 706-715.
  73. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, et al. (2010) Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia. NeurosciBehavPhysiol 40: 737-743.
  74. Malyshev IY, Wiegant FA, Mashina SY, Torshin VI, Goryacheva AV, et al. (2005) Possible use of adaptation to hypoxia in Alzheimer's disease: a hypothesis. Med SciMonit 11: 31-38.
  75. Zhang K, Zhu L, Fan M (2011) Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases. Front MolNeurosci 4: 5.
  76. Thielke S, Slatore CG, Banks WA (2015) Association Between Alzheimer Dementia Mortality Rate and Altitude in California Counties. JAMA Psychiatry 72: 1253-1254.
  77. Manukhina EB, Downey HF, Shi X, Mallet RT (2016) Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease. ExpBiol Med (Maywood) 241: 1351-1363.
  78. Sommerlad A, Sabia S, Singh-Manoux A, Lewis G, Livingston G (2019) Association of social contact with dementia and cognition: 28-year follow-up of the Whitehall II cohort study. PLoS Med 16: 1002862.
  79. Krell-Roesch J, Syrjanen JA, Vassilaki M, Machulda MM, Mielke MM, et al. (2019) Quantity and quality of mental activities and the risk of incident mild cognitive impairment. Neurology 93: 548-558.
  80. Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, et al. (2019) Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA 322: 430-437.
  81. Di MA, Jelinek J, Lauretti E, Curtis ME, Issa JJ, et al. (2019) Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology. Mol Psychiatry.
  82. Honda T, Ohara T, Shinohara M, Hata J, Toh R, et al. (2019) Serum elaidic acid concentration and risk of dementia: The Hisayama Study. Neurology 93: 2053-2064.
  83. Faraco G, Hochrainer K, Segarra SG, Schaeffer S, Santisteban MM, et al. (2019) Dietary salt promotes cognitive impairment through tau phosphorylation. Nature. 574: 686-690.
  84. Nagpal R, Neth BJ, Wang S, Craft S, Yadav H (2019) Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment. EBioMedicine 47: 529-542.
  85. Park J, Tolea MI, Sherman D, Rosenfeld A, Arcay V, et al. (2019) Feasibility of Conducting Nonpharmacological Interventions to Manage Dementia Symptoms in Community-Dwelling Older Adults: A Cluster Randomized Controlled Trial. Am J Alzheimers Dis Other Demen35: 1533317519872635.
  86. Spildooren J, Speetjens I, Abrahams J, Feys P, Timmermans A (2019) A physical exercise program using music-supported video-based training in older adults in nursing homes suffering from dementia: a feasibility study. Aging ClinExp Res 31: 279-285.
  87. McCurry SM, Pike KC, Vitiello MV, Logsdon RG, Larson EB, et al. (2011) Increasing walking and bright light exposure to improve sleep in community-dwelling persons with Alzheimer's disease: results of a randomized, controlled trial. J Am GeriatrSoc 59: 1393-1402.
  88. Arendash G, Cao C, Abulaban H, Baranowski R, Wisniewski G, et al. (2019) A Clinical Trial of Transcranial Electromagnetic Treatment in Alzheimer's Disease: Cognitive Enhancement and Associated Changes in Cerebrospinal Fluid, Blood, and Brain Imaging. J Alzheimers Dis 71: 57-82.
  89. Athanasopoulos D, Karagiannis G, Tsolaki M (2016) Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics. AdvNutr 7: 917-927.
  90. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, et al. (2009) Physical activity, diet, and risk of Alzheimer disease. JAMA 302: 627-637.

Citation: Pei YX, Xiang C, Ling ZL (2020) Clinical Progress in Facilitating Therapy for Alzheimer's Disease?Non-Invasive Treatment,  J Alzheimers Neurodegener Dis 6: 037.

Copyright: © 2020  YUE Xiang Pei, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Herald Scholarly Open Access is a leading, internationally publishing house in the fields of Sciences. Our mission is to provide an access to knowledge globally.



© 2024, Copyrights Herald Scholarly Open Access. All Rights Reserved!