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Neuroregeneration and Dementia: New Treatment Options Smaranda Ioana Mitran1,2†, Bogdan Catalin1,2†, Veronica Sfredel1,2 and Tudor-Adrian Balseanu1,2,3*

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Neuroregeneration and Dementia: New Treatment Options Smaranda Ioana Mitran1,2†, Bogdan Catalin1,2†, Veronica Sfredel1,2 and Tudor-Adrian Balseanu1,2,3* Mitran et al. Journal of Molecular Psychiatry 2013, 1:12 http://www.jmolecularpsychiatry.com/content/1/1/12 JMP REVIEW Open Access Neuroregeneration and dementia: new treatment options Smaranda Ioana Mitran1,2†, Bogdan Catalin1,2†, Veronica Sfredel1,2 and Tudor-Adrian Balseanu1,2,3* Abstract In the last years, physiological aging became a general concept that includes all the changes that occur in organism with old age. It is obvious now, that in developing and developed countries, new health problems concerning older population appear. One of these major concerns is probably dementia. Sooner or later, all forms of dementia lead to learning deficit, memory loss, low attention span, impairment of speech and poor problem solving skills. Normal ageing is a physiological process that also involves a lot of neurological disorders with the same type of symptoms and effects that many researchers are trying to minimize in demented patients. In this review we try to highlight some of the newest aspects of therapeutic strategies that can improve natural neuroregeneration. Keywords: Neuroregeneration, Ageing, Dementia, Dementia therapy Introduction memory function [1,2] but also to poor recovery after With longer life span, especially in developing and devel- stroke [3]. oped countries, new health problems concerning specific Neurodegeneration is a progressive process that occurs needs of older populations arise. One of the major because of a decline in the total number of neurons; health concerns in this aspect is dementia. generally, this process is due to apoptosis and is associ- Dementia is a clinical term used to characterize a ated with a loss of neuronal structure and function [4]. number of diseases with neuropsychiatric symptoms, Ageing is considered the most important risk factor for that are not explained by delirium or major psychiatric brain degeneration and age-related cognitive disorders [5]. disorder and interfere with one's ability to function with Elucidating the cellular and molecular basis of neuro- usual activities [1] but dementia as a biological aspect of degeneration and neuroregeneration and how they are the clinical term has many different causes. involved in the aging brain could reveal new therapeutic All changes that occur in all organs and systems asso- approaches to dementia in the elderly. ciated with old age is now generally accepted as physio- Overall, we aimed at summarizing up to-date findings logical ageing. This concept is characterized by the described and evaluated by a number of different authors declining ability to respond to different types of stress, and by discussing contradictory results of different re- homeostatic imbalance and diseases. searcher groups we want to highlight the complexity of Brain ageing is associated with structures and func- the presented problem. tions decline both is neurons and glia. This is generally referred as neurodegeneration. It is a normal process that can lead to reductions in communication and in Review Neuroregeneration and aging Physiological ageing is now generally accepted as a con- cept that includes all the changes that occur in all organs * Correspondence: [email protected] †Equal contributors and systems associated with old age, characterized by 1Department of Functional Sciences, University of Medicine and Pharmacy, the declining ability to respond to different types of Craiova, Romania stress, homeostatic imbalance and diseases. 2Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy, Craiova, Romania The phenomena involved in brain ageing are associ- Full list of author information is available at the end of the article ated with a decline of the neuronal and glial structures © 2013 Mitran et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitran et al. Journal of Molecular Psychiatry 2013, 1:12 Page 2 of 6 http://www.jmolecularpsychiatry.com/content/1/1/12 and functions, which can lead to reductions in commu- in angiogenesis in cerebrovascular area observed in aged nication and in memory function [1,2] and also to poor mammals [12] can also modify the neurogenic niche by recovery after stroke [3]. decreasing the source of growth factors. Neurodegeneration is a progressive process that occurs because of a decline in the total number of neurons; generally, this process is due to apoptosis and is associated Ageing and dementia with a loss of neuronal structure and function [4]. Ageing As populations get older due to a longer life span, espe- is considered the most important risk factor for brain cially in developing and developed countries, new health degeneration and age-related cognitive disorders [5]. problems concerning specific needs of older populations An increasing susceptibility to poor recovery from arise. One of the major health concerns in this aspect is brain injury has been observed in the elderly. Regener- dementia. ation of neuronal tissue makes no exception however Dementia has many different causes. Dementia is seen the pathways for the cellular processes that characterize as a clinical term used to characterize a number of dis- these phenomena have yet to be found. eases such as Alzheimer's disease dementia, Lewy bodies From a morphological and functional perspective neuro- dementia, vascular dementia, behavior variant fronto- regeneration implies a restorative process involving central temporal dementia, primary progressive aphasia or any nervous system tissue and neural network architecture. cognitive/behavioral changes with neuropsychiatric symp- From a clinical point of view, brain-repairing pathways toms, that are not explained by delirium or major psychi- require the removal of the aetiological factors that caused atric disorder and interfere with one's ability to function the damage after the inflammatory response, to impede with usual activities [1,2]. the degeneration of cells and to restore the neural cells or At the moment it is estimated that 35.6 million people their network [6]. worldwide are diagnosed with dementia. It is predicted The concept of neuregeneration can be also defined as that in approximately 20 years this number will double the superposition of three distinctive processes including and triple in the next 40 years [13]. neurogenesis, neuroplasticity and neurorestoration [7]. It Based on all the information the scientific community is known that the mammalian brain is one of the organs has gathered, the diagnostic criteria for dementia has be- with a very low level of cell replacement. Still, neuro- came more accurate [1,12]. Treatment and management genesis is now generally accepted and neural stem cells of dementia are generated by research based on results have been discovered in different specific brain regions, from studies. Test subjects are patients with early stages including hippocampus [8]. of dementia Figure 1 [14]. As the population gets older, However, older organisms, including humans, have re- new criteria for diagnosing old elderly persons (>75 ported a decline in the rate of neurogenesis. Hippocam- years old) are needed because the border between non pal neurogenesis seems to persist also in adult age. With pathological aged brain and dementia brain is becoming ageing, the proliferation and differentiation of neural more unclear with age [15]. progenitors are significantly decreased with a higher As one gets older, multiple risk factors varying from number of newborn death neurons. childhood IQ [16], obesity in middle age [17], smoking, One possible explanation for this decline can be that hypertension, high cholesterol and diabetes at midlife the neural stem cells are entering in a quiescent state, [18,19] to stroke and atrophy in old age [15] contribute supported by the hypothesis that aged neural stem cells to dementia in the elderly. Scientific progress has found are intrinsically different from the younger one. Another that a small number of highly conserved genes can have possibility can be that the expression of some transcrip- a positive effect on the length of a life span. These genes tion factors (Er81 and Dlx2) associated with neural de- act through a number of metabolic processes like the velopment are reduced in the elderly [9]. “reactive oxygen species” (ROS) representing one of the Another effect can be the reduction in telomerase ac- most incriminated and poorly understood contributors tivity. A study on adult mice deficient in telomerase ac- to brain ageing [20]. Acquiring defense from dietary an- tivity, reported poor neurogenesis in hippocampal areas, tioxidants can protect against ROS induced damage [16]. associated with a lower number of proliferation (Ki67+) It is believed that the brain has a neuronal reserve to or immature (Dcx+) cells [10]. compensate for any loss at old age. However the cause Nevertheless, extrinsic factors from the local environ- of dementia is a more rapid neuronal death as found in ment (neurogenic niche) can regulate neurogenesis. In alcohol abuse, unhealthy eating, smoking, stroke. Re- old age, lower levels for different growth factors that can gardless of the risk factors, dementia is still a con- facilitate neurogenesis (fibroblast growth factor-2, insulin sequence of neuronal populations loss that cannot be growth factor-1 or vascular
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