Alzheimer's Disease and Memory Loss - A Review

Naresh Korrapati^1*, Naga Pavan Kumar B²and Shaik Mohammed Irshad¹

¹Department of Biotechnology, Sri Krishna Devaraya University, Anantapur, India

²Livestock Research Institute, College of Veterinary Science, SVVU, Hyderabad, India

*Corresponding Author:

Naresh Korrapati
Department of Bio-Technology
Sri Krishna Devaraya University
College of Engineering and Technology
Sri Krishna Devaraya University
Anantapur, Andhra Pradesh, India
Tel: +91-9492654991
E-mail: korrapatinaresh991@ gmail.com

Received date August 11, 2016; Accepted date September 02, 2016; Published date September 09, 2016

Citation: Korrapati N, Kumar BNP (2016) Alzheimer�s Disease and Memory Loss - A Review. J Alzheimers Dis Parkinsonism 6: 259. doi: 10.4172/2161- 0460.1000259

Copyright: © 2016 Korrapati N, 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.

Visit for more related articles at Journal of Alzheimers Disease & Parkinsonism

Abstract

Memory loss is one of the first symptoms in patients suffering from Alzheimer’s disease (AD). During the course of the disease patients experience problems with their language, mood swings, and behavioural issues. Due to these conditions patients often withdraw from family or society with the fear and embarrassment and gradually, bodily functions are lost leading to death. The pattern of memory loss correlates with structural and functional integrity of brain. In patients with AD the formation of memory will be affected at molecular level disturbing the framework of neural networks. Recently, many studies have focused on how the AD impacts episodic memory and the underlying neural processes. In this review the findings of these studies are discussed and the effects of current and promising treatments for AD on memory loss are summarized. The main aim of this review is creating awareness in understanding the intact and dysfunctional memory. Moreover the knowledge of a specific process of a particular memory loss due to AD helps the basic scientists in developing novel therapies and drugs.

Keywords

Memory loss; Alzheimer’s disease; Dementia; Acetyl cholinesterase

Introduction

Memory is the ability of an organism to record, retain, and recall events, information and sensory stimuli, over a long or short. Lack or improper memory function can affect the quality of life and the ability to work efficiently. Alzheimer’s disease (AD) has become a synonym for memory loss as it is the most common cause of dementia. Currently, worldwide almost 50 million people suffer from Alzheimer’s dementia and memory loss related diseases and the World Health organization projected this number may even triple over the next 20 years [1-10]. The incidence of Alzheimer dementia increases with an increase in age making it a very common disease in aged person of more than 70. Due to advancements in the medical and biomedical field the longevity of life increased and this made the old aged people to live with Dementia of AD compulsorily [11-15].

Researchers have found six cognitive domains in patients suffering from AD. They are attention and affect, executive functioning, language, memory, visuospatial functioning, and memory impairment is the central problem in the patients. Actually AD is a polygenetic brain disorder which is neurodegenerative in nature and causes neocortical atrophy which develops over decades [16-18].

Opportunities for studying the preclinical stage of Alzheimer’s dementia before diagnosis come rarely. The best way to study dementia in AD is to study persons who are at risk of dementia with high probability. There are is no effective treatments or medicines for AD induced dementia. But progression of the symptomatic development could be prevented and this could be best strategy to mitigate the condition.

Neuropathology of Alzheimer’s

The amyloid deposits called as senile plaques are neuro pathological hallmarks which indicate atrophy process and neurofibrillary tangles in brains of AD patients. Neurofibrillary tangles are hyper phosphorylated tau protein in neurons, whereas senile plaques are amyloid-P species deposited in the extracellular space. Poorly myelinated in neurons of hippocampus, brains cortex which are related to memory and learning are the first signs of AD. Highly myelinated neurons will be affected only in the final phase of AD. Low myelinisation weakens the neurons as it increases the energy expenditure of neurons in nerve transmission. Parietal lobes, and some areas of the prefrontal lobe, are the last areas to mylenate in human brain increasing their vulnerability to AD [19- 25]. Down regulation of synaptic genes in multiple regions of brain, synaptic stress or decay in brain or the cerebrospinal fluid (CSF) and changes in the molecular structure of can be seen in brain resonance spectroscopic studies of AD patients.

Causes of Alzheimer’s Disease

Amyloid β-peptide (Aβ)

Many evidences, suggest that AD is triggered by neurotoxic 42- aa amyloid β-peptide (Aβ) assembly in the brain. Aβ_1-42 is derived by proteolytic cleavage of its precursor protein amyloid precursor protein (APP). Scientists proved that mutations in APP gene can cause familial AD and increases the accumulation of Aβ_1-42 . Aβ_1-42 has the capability of self-association and forms into large, insoluble amyloid fibrils which can be found in AD neuritic plaques. This hypothesis of amyloid cascade was formulated in 1992, which proposed that the primary molecular pathogens of AD are these insoluble amyloid fibrils. But this hypothesis wasn’t accepted. The amyloid cascade hypothesis was rectified by including pathogenic Aβ assemblies, but their structure differs entirely with amyloid fibrils. These assemblies will not be detected by normal assays like that of fibril deposits. Soluble oligomers have been considered to be the culprits for physical degeneration of synapses and in age-onset memory failure [26-30].

Mitochondrial dysfunction

Aβ is considered as a potent mitochondrial poison affecting the synaptic pool [31] In Alzheimer’s patients exposure to Aβ will inhibit many mitochondrial enzymes like Cytochrome C in the brain [32,33]. The accumulation of Aβ in damaged mitochondria of AD in the brains of AD patients intra neuronally can be found [34,35].

ApoE4

In late-onset AD still many unidentified genes are involved, each contributing a minor fraction of disease overall risk, which is an example of antagonistic pleiotropy. Recently, several studies have identified new genes and molecules involved in the onset of dementia in AD. Apolipoprotein is one of the best characterized genetic risk factor in late-onset of AD. Individuals with E4 (ApoE4) genotype or with ApoE4 carriers will have 4-10 fold increased probability of developing AD. Adaption of humans with diet of meat can also be a reason for the selection of ApoE3 for the AD in the evolutionary perspective. The progression of AD is not understood clearly till now [36-43].

Cell-cycle re-entry

Many scientists hypothesized that the failure in the normal suppression of cell cycle as one of the reasons for the onset of Alzheimer’s disease [44]. Bio-markers of cell-cycle reentry especially in G1–S-phase boundary can be detected in all stages of AD and even in mild cognitive impairment [45,46].

Calpain-cathepsin hypothesis

Autophagic vacuoles or granulo-vacuolar degenerations can be seen in degenerating neurons of AD patients. This probably is a causative connection between neuronal death and autophagy failure. Hence, many scientists proposed that an age-dependent oxidative stress affects autophagic-lysosomal system through cleavage and carbonylation of heat-shock protein 70.1 (Hsp70.1). Membrane lipids are vulnerable to the oxidative stresses and they generate toxic peroxidation products that can carbonylate Hsp70.1. Many evidences suggest that Hsp70.1 is a molecular chaperone which repairs damaged proteins and maintains lysosomal integrity.

Impairments of lysosomal functions and stabilization is found to be driven by calpain-mediated cleavage of carbonylated Hsp70.1, which results in lysosomal permeabilization or rupture releasing the cell degradation enzymes, cathepsins which eventually lead to the AD. This hypothesis is called as calpain-cathepsin hypothesis, which is recently put forward by the scientists and currently most acceptable.

Synaptic failure

Many researchers concluded that the Alzheimer’s disease may be disorder of synaptic failure [45]. It is evident that Hippocampal synapses declines even in patients with mild cognitive impairment [46].

Diagnosis of Alzheimer’s Disease

The diagnosis is made on the basis of medical history from the relatives and behavioural, neurological and neuropsychological observations. Magnetic resonance imaging (MRI), Computer Tomography (CT), Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) which can be used in the determining cerebral pathology in AD patients. CCSVI has been evaluated using ECD, UDC, UDS, TCCS, and even MRI. Intellectual quotient can be assessed by memory testing. Application of Echo-color-Doppler technique to detect neuro degeneration can be used to find AD in patients [47-58].

Alzheimer’s Disease Management

There is no prescribed method or form for AD prevention as the Research findings for treating AD have been highly inconsistent. Epidemiological factors of AD were associated with diet habits, cardiovascular diseases, and intellectual activities [59-63].

Presently, AD medications targets only secondary risk factors such as hypercholesterolemia, hypertension, smoking etc. Very few Drugs have shown little success to arrest the progression of AD. Hormone replacement therapy has also been proposed for treating AD but the research suggested that it still increases dementia. Change in lifestyle of AD patients including is recommended as a possible management strategy for AD. Some research findings suggested that Red wine, Caffeine, tea, cocoa, Vitamin A, C, E, Folic acid and minerals such as selenium and Zinc etc., were effective against AD management [64-70].

Some Studies have shown that the levels of Acetyl Cholinesterase (ACh) play an important role in the cognitive function. Recent medication strategies of medication for AD targeted the cholinergic activity improvement in the brain. Therefore, uses of acetyl cholinesterase inhibitors have been reported to improve clinical symptoms of AD. Conventional ACh inhibitors like donepezil, Galantamine, rivastigmine, tacrine, etc., are few examples [71-76].

Herbs in Treating Alzheimer’s Disease

Gingko biloba contain bioactive compounds which promote blood flow in the brain [77-82] which enhances the neurotransmitters keeping the cerebral complex healthy. Currently application of Gingko biloba is done in combination with approved cholinesterase inhibitors despite side effects in using Gingko biloba [83-91].

Lycopodium serratum produces huperzine A, a potential therapeutic agent for treating AD. Huperzine A protects from neuronal apoptosis, Aβ-induced oxidative injury, Aβ mediated oxidative stress, and mitochondrial dysfunction, and reduces glutamate-induced toxicity which helps in clinical improvements of patients with AD [92- 97]. It also reduces toxicity in the neurons by modulation of interaction between glutamate-NMDA receptors. Some other herbs like Curcuma longa, Periwinkle are also being used in treatment for AD [98-100].

Hypericum extract contains flavonoids such as quercitrin and quercetin show potential free radical scavenging activity, antioxidant activity through the inhibition of lipid peroxidation. Hypericum extract in combination with scopolamine has been proved to show antidepressant activity with memory-enhancing capability which can be used in treating AD. P. tenuifolia a traditional Chinese medicinal herb is used as tranquillizer for treating and preventing dementia in combination with scopolamine this herb is potential in treating AD.

C. paniculatus (Celastraceae) an Indian medicinal plant mainly used in the traditional Ayurvedic system for stimulating nerves, and as a diuretic, rejuvenant, tranquilizer etc., needs to explored for its potential in treating AD. Herbs like Ginseng, M. officinalis (lemon balm), Salvia officinalis, Lavandula officinalis, Zizyphus jujube, Lepidium meyenii, Prunella vulgaris, Curcumin, etc., were also proved to be having potential therapeutic effect on AD.

Conclusion

The number of AD patients is increasing every day. Unfortunately this disease has not known potential treatment methodologies or drugs. Intensive research and new interventions using latest monitoring and diagnostic tools for AD are required to cure the disease progression. Herbs are promising in AD treatment which is another dimension needed to be focused. Many of the traditional herbs which have potent antioxidant and neuro protective effects needs to be further studied to identify novel therapeutic bioactive compounds for the treatment of AD.

References

1. Archer T (2016) Amelioration of symptoms and biomarkers of alzheimers disease by physical exercise. Open Access 2:e105.
2. Woods JJ, Martin KL, Acquah EF, Smith M, Hansbro PM, et al. (2016) Cigarette smoking: A causal factor for alzheimers disease? JGerontolGeriatr Res 5:286.
3. Allen HB, Morales D, Jones K, Joshi S (2016) Alzheimer’s disease: A novel hypothesis integrating spirochetes, biofilm and the immune system. J Neuroinfect Dis 7:200.
4. Allen HB, Shaver CM, Etzler CA, Joshi SG (2015) Autoimmune diseases of the innate and adaptive immune system including atopic dermatitis, psoriasis, chronic arthritis, Lyme disease and Alzheimer’s disease. ImmunochemImmunopathol 1:112.
5. Zhou LL (2015) GluN2B-NMDA receptors in Alzheimer’s disease: What do they got to do with AD? J NeurolDisord 3:e118. 
6. Juma KK (2015) A current understanding of alzheimer’s disease and the prospects of phytopharmacological intervention as a management strategy. J NeurolDisord 3:244.
7. Ryan JJ, Kreiner DS, Seeley JS, Paolo AM (2015) Temporal disorientation base rates in Alzheimer’s disease and Parkinson’s disease. J GerontolGeriat Res 4:221.
8. Miller MD, Morycz RK (2015) Preparing for the rise in Alzheimer’sdisease cases: A proposal for training support personnel. J GerontolGeriatr Res 4:195.
9. Kim H, Shin A, Joon Lee K (2015) Differences in C-reactive protein level in patients with Alzheimer’s disease and mild cognitive impairment. J Psychiatry 18:194.
10. Tian M, Zeng Y, Sun L, Wu Q (2014) Alzheimer’s disease and dementia, under-recognized public health crisis in China. J GerontolGeriat Res 3:162.
11. Block A, Dhanasekaran AR, Ahmed MM, Gardiner KJ (2014) Abnormal protein profiles in hippocampus of mouse models of Down syndrome: Similarities with Alzheimer’s disease. J Alzheimers Dis Parkinsonism 4:138.
12. Manaye KF, William Rebeck G (2013) Possible APOE genotype and sex dependent effects of 17-a- estradiol on Alzheimer’sdisease pathology. J Alzheimers Dis Parkinsonism 3:e130.
13. Tarumi T, Tanaka H (2012) Alzheimer’s disease and habitual exercise: Relationship mediated and fostered by vascular risk profiles? J Gerontol Geriatric Res 1:e111.
14. Singh I (2012) Challenges to establish definite diagnosis of Alzheimer’s disease. J Gerontol Geriatric Res 1:e105.
15. Lukiw WJ (2012) Towardseffective treatment strategies for Alzheimer’s disease (AD). J Develop Drugs 1:e102.
16. Choudhary S(2015) Memory loss in elderly: A clear view. GerontolGeriatr Res S4:008.
17. Thaler A, Siry R, CaiL, Garcia PS, Chen L, et al. (2012) Memory loss, Alzheimer’s disease and general anesthesia: A pre-operative concern. J Anesthe Clinic Res 3:192.
18. Avila J (2011) A possible role for GSK3 in the impaired neurogenesis and memory loss associated with Alzheimer’s disease and aging. J Alzheimers Dis Res 1:102e.
19. Archer T, Garcia D (2016) Selective diets for dementia disorders. ClinExpPsychol 2:127.
20. Garden G (2016) Theimpact of advance care planning for care home residents with dementia on hospital admission and death in preferred place of care. J Palliat Care Med 6:261.
21. Tobe EH (2016) Geriatric traumatic brain injury: relationship to dementia and neurodegenerative disease. J GerontolGeriatr Res 5:292.
22. Sherzai D, Sherzai A, Sahak M, Ani C (2016) Age and race specific trends and mortality for dementia hospitalization in the US. J NeurolNeurophysiol 7:358.
23. Tsuno N (2016) Thepotential role of donepezil for the treatment of dementia with lewy bodies. J Alzheimers Dis Parkinsonism 6:214.
24. Suzuki H, Inoue Y (2015) Acomparison of lamotrigine or sodium valproate on the efficacy in Alzheimer’s disease with behavioral and psychological symptoms of dementia: A retrospective open-label study running title: Efficacy of anticonvulsants for BPSD. J GerontolGeriatr Res 4:253. 
25. Schwartz M, Serrano G, Beach TG, Tsai A, Malek-Ahmadi M, et al. (2016) Neurofibrillarytangle predominant dementia: Clinical and pathological description in a case series. J Alzheimers Dis Parkinsonism 6:204.
26. Brodziak A, Ziolko E (2016) Medical and mental target risk factors for dementia prevention. J GerontolGeriatr Res 5:266. 
27. Desin PJ, Caban-Holt AM, Abner EL, Van Eldik LJ, Schmitt FA (2016) Factors associated with unmet needs among African-American dementia care providers. J GerontolGeriatr Res 5:267.
28. Wang H (2016) Vascularhealth promotion project and vascular dementia prevention in China. J Alzheimers Dis Parkinsonism 6:210. 
29. Ling TL (2016) Challenging aspects of bereavement and grief in older adults with dementia: A case series and clinical considerations. J GerontolGeriatr Res 5:276.
30. Pfrommer ME, McConnell ES, Diepold JH, Siegert EA, Thompson AA (2015) Heart assisted therapy-self-regulation (HAT-SR) for caregivers of persons with dementia. GerontolGeriatr Res S4:005.
31. Mungarro-Menchaca X, Ferrera P, Moran J, Arias C (2002)Beta-amyloid peptide inducesultra structural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine. J Neurosci Res 68:89-96.
32. Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45-53.
33. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, et al. (2005) Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunctionin Alzheimer’s disease. FASEB J 19: 2040-2041.
34. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, et al. (2001) Mitochondrial abnormalities in  Alzheimer’s disease. J Neurosci21:3017-3023.
35. Gouras GK, Almeida CG, Takahashi RH (2005)IntraneuronalAbeta accumulationand origin of plaques in Alzheimer’s disease. Neurobiol Aging 26:1235-1244.
36. Ishiwata A, Nito C, Kimura K (2015) Lewybody dementia as an underlying etiology for posterior cortical atrophy initially presented with visual agnosia and alexia: A case report. J NeurolNeurophysiol 6:305.
37. Luo P, Guo L (2015) HCN channels: From the role in chronic cerebral hypoperfusion-induced cognitive impairments to a new therapeutic target for vascular dementia. J NeurolNeurophysiol 6:308.
38. Jellinger KA (2015) Thediabetic brain and dementia. J Alzheimers Dis Parkinsonism 5:193.
39. Leon AM (2015) Dementias: Turning to slowing of background plotting a frequency subalf. J Alzheimers Dis Parkinsonism 5: i101.
40. Ansari I,GrossbergGT(2015) Syphilis a reversible cause of dementia. J GerontolGeriatr Res S4:003.
41. Naguy A, Al-Tajali A, Al-Mutairi H (2015) Acamprosatecomplements ill-sustained response of ECT in catatonic fronto-temporal dementia. J Psychiatry 18:292.
42. Jones RP (2015) Unexpected increase in deaths from Alzheimer’s, dementia and other neurological disorders in England and Wales during 2012 and 2013. J Neuroinfect Dis 5:172.
43. Meyer C, Hill K, Hill S, Dow B (2015) Translating falls prevention knowledge for community-dwelling people living with dementia: Design protocol for a mixed-method intervention. J Alzheimers Dis Parkinsonism 5:185.
44. Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s dis-ease brain. J Neurosci18:2801-2807.
45. Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all  stages  of Alzheimer’s disease. J Neurosci23:2557-2563.
46. Liu DX, Greene LA (2001) Neuronal apop-tosis at the G1/S cell cycle checkpoint. Cell Tissue Res 305:217-228.
47. Park AL (2014) Isthere anything special about intergenerational approaches to older people with dementia? A review. J Alzheimers Dis Parkinsonism 4:172.
48. Hori K, Konishi K, Tani M, Akashi N, Kitajima Y, et al. (2015) Anti-dementia agents are partially symptomatic treatment and partially disease modifying treatment. Brain DisordTher 4:148.
49. Tortolero GS, Fragoso M, Espanol G, Estevez M, Rey A (2015) EEG findings in diffuse lewy body disease and Parkinson’s disease with dementia. Brain DisordTher 4:156.
50. Ono K, Kanayama Y, Iwata M, Yabuwaki K (2014) Views on co-occupation between elderly persons with dementia and family. J GerontolGeriatr Res 3:185.
51. Hvidsten L, Engedal K, Selbaek G, Wyller TB, Høgh P (2015) Young onset dementia study – A prospective cohort study of quality of life and specific needs in persons with young onset dementia and their families. J Clin Trials 5:204. 
52. Hirakawa Y (2014) Emotional and spiritual pain and suffering of older people with end-of-life dementia from the perspective of nurses and care workers: A qualitative study. J Nurs Care 3:212.
53. Amr M, El-Gilany AH, Sallam K, Shams T (2014) Characteristics of patients with dementia attended in a tertiary outpatient clinic in eastern region, Saudi Arabia. J Psychiatry 17:143.
54. Safi AJ, Hodgson NA (2014) Timing of activities and their effects on circadian rhythm in the elderly with dementia: A literature review. J Sleep DisordTher 3:176.
55. Liu MF, Buckwalter K, Burgener S (2014) Perceived stigma in caregivers of persons with dementia and its impact on depressive symptoms. J Depress Anxiety 3:162.
56. Xu X, Rahardjo TB, Xiao SF, Hogervorst E (2014) The Hopkins verbal learning test and detection of MCI and mild dementia: A literature review. J Alzheimers Dis Parkinsonism 4:166.
57. Ikemoto K, Nishimura A, Nishi K (2014) Lectin-positive spherical deposits (SPD) detected in the molecular layer of hippocampal dentate gyrus of dementia, Down syndrome and schizophrenia. J Alzheimers Dis Parkinsonism 4:169.
58. Rakesh B, Bharath S, Bagepally BS, Saini J, Sadanand S, et al. (2014) A retrospective study on relation between cognitive performance and lobar perfusions of brain in Alzheimer’s dementia using single photon emission computer tomography. Brain DisordTher 3:135.
59. Mizuno D, Kawahara M (2014) Carnosine: A possible drug for vascular dementia. J Vasc Med Surg 2:146.
60. Rokstad AMM, Halse I, Tretteteig S, Barca ML, Kirkevold O, et al. (2014) Effects and costs of a daycare centre program designed for people with dementia–A 24 month controlled study. J Clin Trials 4:182. 
61. Remes AM (2014) Functional MRI in patients with the C9ORF72 expansion associate frontotemporaldementia. MolBiol 3:117. 
62. Tanaka H, Hori K, Inamoto A (2014) Relationship with bipolar temperament and behavioral and psychological symptoms of dementia in Alzheimer’s disease. Brain DisordTher 3:144.
63. Hu WT, Hazim M, Hales CM, Lah JL, Levey AI (2014) CSF and neuropsychological correlates of visual hallucination in dementia with lewy bodies. J NeurolNeurophysiol 5:238.
64. Clionsky M, Clionsky E (2014) Dementia screening: Saying no to the USPSTF and yes to brief cognitive evaluation. J Alzheimers Dis Parkinsonism 4:e132. 
65. Jones GR (2014) Therole of acetaminophen in the development of dementia. J Allergy Ther 5:172.
66. Reiber H, Lange P, Zerr I (2014) Neurochemical dementia diagnostics – Interlaboratoryvariation of analysis, reference ranges and interpretations. J Alzheimers Dis Parkinsonism 4:147.
67. Truswell D (2014) Black, Asian and minority ethnic communities and dementia – Where are we now? J Alzheimers Dis Parkinsonism 4:152.
68. Ahmad MY, Lukman FO, Mustafa IG, Aliyu I, Hamza M, et al. (2014) Performance of community screening instrument for dementia in screening for HIV-associated neurocognitive disorders in Nigeria. J Neuroinfect Dis 5:157.
69. Cacabelos R, Goldgaber D, Vostrov A, Matsuki H, Torrellas C, et al. (2014) APOE-TOMM40 in the pharmacogenomics of dementia. J Pharmacogenomics Pharmacoproteomics 5:135.
70. Kogoj A, Prokšelj T (2013) Do we know all about behavioral and psychological symptoms of dementia? J GerontolGeriat Res 3:e124. 
71. Mathur T, Mathur S (2014) A case of glioblastomamultiforme masquerading as rapidly progressive dementia. Brain DisordTher 3:113. 
72. Jellinger KA (2014) Neuropathology of dementia disorders. J Alzheimers Dis Parkinsonism 4:135.
73. Lu GM, Brew BJ, Siefried KJ, Draper B, Cysique LA (2013) Is the HIV dementia scale a reliable tool for assessing HIV-related neurocognitive decline? J AIDS Clin Res 5:269.
74. Kada S (2013) Quality of life of nursing home residents: A comparative study of persons with and without dementia in regular units and persons with dementia in different care settings. J GerontolGeriat Res 2:129.
75. Perry EA, Perry G, Castellani RJ, Moreira PI (2012) Failure of Aßremoval to improve Alzheimer’s dementia opens the door to new thinking. J Alzheimers Dis Parkinsonism 2:e126.
76. Ahmed T, Gilani AU, Abdollahi M, Daglia M, Nabavi SF, et al. (2015) Berberine and neurodegeneration: A review of literature.Pharmacol Rep 67: 970-979.
77. Dar NJ, Hamid A, Ahmad M (2015) Pharmacologic overview of Withaniasomnifera, the Indian ginseng. Cell Mol Life Sci 72: 4445-4460.
78. Yeh CW, YehSH, Shie FS, Lai WS, Liu HK,et al. (2015) Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe/PS1dE9 mice.Neurobiol Aging 36: 2984-2994.
79. Dong XH, Bai JT, Kong WN, He XP, Yan P, et al. (2015) Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload. Neural Regen Res 10: 778-785.
80. Hugel HM (2015) Brain food for Alzheimer-free ageing: Focus on herbal medicines. AdvExp Med Biol 863: 95-116.
81. Ambrée O,Klassen I, Förster I, AroltV, Scheu S, et al. (2016) Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice. Behav Brain Res S0166-4328: 30476-30484.
82. Newman MG, Shin KE, Zuellig AR (2016) Developmental risk factors in generalized anxiety disorder and panic disorder. J Affect Disord 206: 94-102.
83. Rich MT, Abbott TB, Chung L, Gulcicek EE, Stone KL, et al. (2016) Phosphoproteomicanalysis reveals a novel mechanism of CaMKIIa regulation inversely induced by cocaine memory extinction versus reconsolidation. J Neurosci 36: 7613-7627.
84. Xu D, Chen H, Mak S, Hu S, Tsim KW,et al. (2016) Neuroprotection against glutamate-induced excitotoxicity and induction of neurite outgrowth by T-006, a novel multifunctional derivative of tetramethylpyrazine in neuronal cell models.NeurochemInt S0197-0186: 30218-30222.
85. McKinnon MC, Boyd JE, Frewen PA, Lanius UF, Jetly R,et al. (2016) A review of the relation between dissociation, memory, executive functioning and social cognition in military members and civilians with neuropsychiatric conditions. Neuropsychologia S0028-3932: 30261-30265.
86. Moretti DV (2016) Electroencephalography-driven approach to prodromal Alzheimer's disease diagnosis: From biomarker integration to network-level comprehension. ClinInterv Aging 11: 897-912.
87. Alberdi A, Aztiria A, Basarab A (2016) On the early diagnosis of Alzheimer's Disease from multimodal signals: A survey. ArtifIntell Med 71: 1-29.
88. Rivera DS, Lindsay C, Codocedo JF, Morel I, Pinto C, et al. (2016) Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodondegus).Neurobiol Aging 46: 204-220.
89. Arbor SC, LaFontaine M, Cumbay M (2016) Amyloid-beta Alzheimer targets - Protein processing, lipid rafts and amyloid-beta pores.Yale J Biol Med 89: 5-21.
90. Ohrfelt A, Johansson P, Wallin A, Andreasson U, Zetterberg H, et al. (2016) Increased cerebrospinal fluid levels of ubiquitin carboxyl-terminal hydrolase L1 in patients with Alzheimer's disease. Dement GeriatrCogn Dis Extra 6: 283-294.
91. McKeith I, Taylor JP, Thomas A, Donaghy P, Kane J (2016) Revisiting DLB diagnosis: A consideration of prodromal DLB and of the diagnostic overlap with Alzheimer disease. J Geriatr Psychiatry Neurol 29: 249-253.
92. Huang L, Jin Y, Gao Y, Thung KH, Shen D (2016) Longitudinal clinical score prediction in Alzheimer's disease with soft-split sparse regression based random forest. Neurobiol Aging 46: 180-191.
93. Fu X, Wang Q, Wang Z, Kuang H, Jiang P (2015) Danggui-Shaoyao-San: New hope for Alzheimer's Disease.Aging Dis 7: 502-513.
94. Santos-Lozano A, Pareja-Galeano H, Sanchis-Gomar F, Quindós-Rubial M, Fiuza-Luces C, et al. (2016) Physical activity and Alzheimer disease: A protective association. Mayo ClinProc 91: 999-1020.
95. Anderson ED, Wahoske M, Huber M, Norton D, Li Z, et al. (2016) Cognitive variability-A marker for incident MCI and AD: An analysis for the Alzheimer's disease neuroimaging initiative.Alzheimers Dement (Amst) 4: 47-55.
96. Kandel BM, Avants BB, Gee JC, McMillan CT, Erus G, et al. (2016) White matter hyper intensities are more highly associated with preclinical Alzheimer's disease than imaging and cognitive markers of neurodegeneration. Alzheimers Dement (Amst) 4: 18-27.
97. Combs CK, Karlo JC, Kao SC, Lan-dreth GE (2001)Beta-amyloid stimulation of microglia and   monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 21:1179-1188.
98. Licastro F, Porcellini E (2016) Persistent infections, immune-senescence and Alzheimer's disease. Oncoscience 3: 135-142.
99. Gago MF, Yelshyna D, Bicho E, Silva HD, Rocha L, et al. (2016) Compensatory postural adjustments in an oculus virtual reality environment and the risk of falling in Alzheimer's disease. Dement GeriatrCogn Dis Extra 6: 252-267.
100. Wang ZM, Cai P, Liu QH, Xu DQ, Yang XL, et al. (2016) Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease. Eur J Med Chem 123: 282-29 7.