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There was exactly one that appeared to show an association. It was later found to be a fraud, with fudged data, cherry picked patients, and not one but two undisclosed financial interests. He took money from lawyers to get those results, and was also trying to make his own vaccine patent look good in comparison.It still caused concern though, which is why since then, millions of research dollars have been spent (wasted) trying to replicate the results. They haven’t. At this point millions of children have been tracked including every child born in the country of Denmark over a 10 (Edit: actually 28) year period. There’s no correlation, no association, no cause. Below is a sampling of the studies that have found that vaccines don’t cause autism.In fact, we now know not only that it doesn’t, but also that it can’t. We can now detect autism before the first set of vaccinations.Edit: Wait there was another study that claimed to find evidence of a link between vaccines and autism in African American boys. They used the “covered up” yet totally publicly available CDC data.[FACT CHECK: Fraud at the CDC Uncovered?]And here’s the article….whoops…The retraction statement:The Editor and Publisher regretfully retract the article [1] as there were undeclared competing interests on the part of the author which compromised the peer review process. Furthermore, post-publication peer review raised concerns about the validity of the methods and statistical analysis, therefore the Editors no longer have confidence in the soundness of the findings. We apologise to all affected parties for the inconvenience caused.So once again, someone was fudging statitistics for money.Now to the studies that showed NO LINK. They come from industry, academic, and government researcher across multiple countries:Abu Kuwaik G, Roberts W, Zwaigenbaum L, Bryson S, Smith IM, Szatmari P, Modi BM, Tanel N, Brian J. Immunization uptake in younger siblings of children with autism spectrum disorder. Autism. 2014 Feb;18(2):148-55. doi: 10.1177/1362361312459111. Epub 2012 Oct 8. PubMed PMID: 23045216.Albizzati A, Morè L, Di Candia D, Saccani M, Lenti C. Normal concentrations of heavy metals in autistic spectrum disorders. Minerva Pediatr. 2012 Feb;64(1):27-31. PubMed PMID: 22350041.Afzal MA, Ozoemena LC, O’Hare A, Kidger KA, Bentley ML, Minor PD. Absence of detectable measles virus genome sequence in blood of autistic children who have had their MMR vaccination during the routine childhood immunization schedule of UK. J Med Virol. 2006 May;78(5):623-30. PubMed PMID: 16555271.Ahearn WH. What Every Behavior Analyst Should Know About the “MMR Causes Autism” Hypothesis. Behav Anal Pract. 2010 Spring;3(1):46-50. PubMed PMID: 22479671; PubMed Central PMCID: PMC3004684.Allan GM, Ivers N. The autism-vaccine story: fiction and deception? Can Fam Physician. 2010 Oct;56(10):1013. PubMed PMID: 20944043; PubMed Central PMCID: PMC2954080.Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004 Sep;114(3):584-91. PubMed PMID: 15342825.Andrews N, Miller E, Taylor B, Lingam R, Simmons A, Stowe J, Waight P. Recall bias, MMR, and autism. Arch Dis Child. 2002 Dec;87(6):493-4. PubMed PMID: 12456546; PubMed Central PMCID: PMC1755823.Aps LRMM, Piantola MAF, Pereira SA, Castro JT, Santos FAO, Ferreira LCS. Adverse events of vaccines and the consequences of non-vaccination: a critical review. Rev Saude Publica. 2018;52:40. doi: 10.11606/s1518-8787.2018052000384. Epub 2018 Apr 12. Review. Portuguese, English. PubMed PMID: 29668817; PubMed Central PMCID: PMC5933943.Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, Kurzius-Spencer M, Zahorodny W, Robinson Rosenberg C, White T, Durkin MS, Imm P, Nikolaou L, Yeargin-Allsopp M, Lee LC, Harrington R, Lopez M, Fitzgerald RT, Hewitt A, Pettygrove S, Constantino JN, Vehorn A, Shenouda J, Hall-Lande J, Van Naarden Braun K, Dowling NF. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years – Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018 Apr 27;67(6):1-23. doi: 10.15585/mmwr.ss6706a1. PubMed PMID: 29701730.Baird G, Pickles A, Simonoff E, Charman T, Sullivan P, Chandler S, Loucas T, Meldrum D, Afzal M, Thomas B, Jin L, Brown D. Measles vaccination and antibody response in autism spectrum disorders. Arch Dis Child. 2008 Oct;93(10):832-7. doi: 10.1136/adc.2007.122937. Epub 2008 Feb 5. Erratum in: Arch Dis Child. 2008 Dec;93(12):1079. PubMed PMID: 18252754.Berger BE, Navar-Boggan AM, Omer SB. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination–United States, 2001-2010. BMC Public Health. 2011 May 19;11:340. doi: 10.1186/1471-2458-11-340. PubMed PMID: 21592401; PubMed Central PMCID: PMC3123590.Black C, Kaye JA, Jick H. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. BMJ. 2002 Aug 24;325(7361):419-21. PubMed PMID: 12193358; PubMed Central PMCID: PMC119436.Black SB, Cimino CO, Hansen J, Lewis E, Ray P, Corsaro B, Graepel J, Laufer D. Immunogenicity and safety of measles-mumps-rubella, varicella and Haemophilus influenzae type b vaccines administered concurrently with a fourth dose of heptavalent pneumococcal conjugate vaccine compared with the vaccines administered without heptavalent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2006 Apr;25(4):306-11. 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At the bottom, I’ve pasted an incomplete list, pulled from Vaccines and autism – science says they are unrelated. There are 145.In every case, there was a failure to show any correlation between vaccines and autism. When you look at the meta-analysis that comes from these studies, there have now been several million children studied. If there was a correlation, they would have found it.Based on the phrasing of the question, I suspect the “gotcha” that you can’t prove a negative. Yes, it’s true that if in 1 in 10,000,000 children, there is something super special that causes a link to be real, these studies wouldn’t have found it. But then, you could literally say that about anything, including air travel, eating avocados, or exposing the child to Teletubies, breast feeding, not breast feeding, use of nightlights, sleeping in the dark…. It becomes a rediculous fishing expedition.Even with all that, the epidemiological evidence is pretty much rendered moot by the developmental and genetic evidence. We now know that autism is 83–90% genetic [New Research Says the Risk for Autism Spectrum Disorder is Mostly Genetic]. Your height has a smaller genetic component (60–80%). We also have new techniques that can detect autism before the first vaccination. [Diagnosing Infants].We’ve reached the point that any claim that one causes the other means it has to be a statistically insignificant cause, and that the vaccine somehow reaches backward in time to cause it. I guess among the scary additives they put in the shots, they should have left out the tiny tardises.Abu Kuwaik G, Roberts W, Zwaigenbaum L, Bryson S, Smith IM, Szatmari P, Modi BM, Tanel N, Brian J. Immunization uptake in younger siblings of children with autism spectrum disorder. Autism. 2014 Feb;18(2):148-55. doi: 10.1177/1362361312459111. Epub 2012 Oct 8. 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Neurogenesis does not replace dead neurons individually. They are translocated in a general sense. Here is an excerpt out of my honours thesis, focusing on the subventricular zone. Note PSA-NCAM is one of a few molecules that help neurons migrate. Without PSA, NCAM expressing neurons would ‘stick’ to the ventricular wall for instance and not undergo migration. Other neuronal factors also regulate the process.IntroductionHistorical overview of neurogenesis in the adult mammalian brainNeurogenesis is the process by which new neurons are formed in the brain, arising from neural stem cells (NSCs) and neural progenitor cells (NPCs) (Curtis et al., 2012). Neurogenesis involves the proliferation of neuronal precursor cells, followed by their migration into the appropriate brain region, survival and differentiation into functional neurons (Ming and Song, 2005; Curtis et al., 2012).Historically, it was thought that the adult brain consisted solely of neurons formed during development and that no new neurons could be generated after birth. This view began to be challenged by experiments that suggested new neurons could be formed in the adult brain. Altman and Das (1965) used 3H thymidine, which incorporates into dividing cells during S phase, to detect mitotic cells in the subgranular zone (SGZ) of the dentate gyrus (DG) and SVZ of adult rats, before identifying the olfactory bulb (OB) as the major target of migrating neuronal precursors from the SVZ (Altman, 1969).Neurogenesis in the adult human was first confirmed to occur in the DG using immunohistochemistry, where cells were double labelled with 5-bromo-2’-deoxyuridine (BrdU), a thymidine analogue that incorporates into dividing cells in S phase (Dean et al., 1984), and NeuN, a mature neuronal marker to indicate that the dividing cells carried a neuronal phenotype (Eriksson et al., 1998). In the postnatal human SVZ, neuroblast-like cells expressing migratory marker polysialylated neural cell adhesion molecule (PSA-NCAM), but not glial markers, were also detected (Weickert et al., 2000), indicating immature neurons are present in this region well after birth.Functionally, neurogenesis enables replacement of granule cell neurons in the DG of the hippocampus and of interneurons in the OB (Kaplan et al., 1985). New neurons may play roles in memory and plasticity in the hippocampus, as neurogenesis is increased in mice exposed to an enriched environment (Kempermann et al., 1997). Neurogenesis is also important for song acquisition and memory in songbirds (Alvarez-Buylla et al., 1992). The addition of new neurons in the OB appears to control odour discrimination (Gheusi et al., 2000) as disrupting NPC migration to the OB impairs this ability. While it is not known whether neurogenesis has functional significance in humans during adulthood, this is inferred based on animal models. However, altered neurogenesis is associated with many neurodegenerative disorders, such as Alzheimer’s Disease and Parkinson’s Disease (Curtis et al., 2012), where memory and cognition is known to be impaired.Neurogenesis in the Subventricular ZoneThe SVZ is derived embryonically from the medial and lateral ganglionic eminences (Brazel et al., 2003). In both humans and rodents, the SVZ runs directly beneath the ependymal layer along the lateral wall of the lateral ventricles (Sanai et al., 2004). Structurally, the adult human SVZ can be divided into four major layers, each housing particular cell types (Figure 1). The outermost layer (1) consists of ependymal cells in contact with cerebrospinal fluid (CSF) of the lateral ventricles, followed by a hypocellular gap layer (2), consisting of astrocytic processes and expansions of ependymal cells (Quinones-Hinojosa et al., 2006). This layer is absent in rodents (Sanai et al., 2004). Lateral to this lies an astrocytic ribbon layer (3), aptly named because NSCs express typical astrocytic markers including glial fibrillary acidic protein (Doetsch et al., 1999), glutamate-aspartate transporter and nestin (Kriegstein and Alvarez Buylla, 2009). The NSCs, called Type B cells, are considered the primary progenitors of new neurons (Doetsch et al., 1999; Imura et al., 2003). These divide infrequently into Type C cells, known as transient amplifying progenitors (TAPs), which proliferate to form layer 4. Type C cells then give rise to Type A neuroblasts, which travel to layer 2 before undergoing tangential migration along the rostral migratory stream (RMS) to reach the OB (Figure 2). This primary migratory route of neuroblasts has been characterised by Sanai et al. (2004) and Wang et al. (2011) in both the adult monkey, as well as fetal humans. Sanai et al. (2011) also identified a secondary route in humans, called the medial migratory stream, whereby neuroblasts travel to the ventromedial prefrontal cortex. This pathway was not observed six months after birth , suggesting migration pathways may change with ageFigure 1: Layers of the SVZ and associated cell types in the adult human (Curtis et al., 2012). The SVZ can be subdivided into four layers which house particular cell types. The outermost layer (1) is comprised of ependymal cells, followed by a hypocellular gap layer (2), then an astrocytic ribbon layer (3), where Type B NSCs reside. These generate Type C TAPs in layer 4. From TAPs, Type A neuroblasts are generated which migrate to layer 2 before running through the RMS.Figure 2: Sagittal section showing the neurogenic regions (circled in red) as they occur in the adult rodent (adapted from Abrous et al. (2005)). The SVZ lines the lateral wall of the lateral ventricles and is the source of proliferative cells. Neuroblasts from the SVZ undergo migration through the RMS to the OB. These neuroblasts then differentiate into OB interneurons. Neurogenesis also occurs in the SGZ of the DG.While it is established that new neurons continue to be formed postnatally, there is still controversy as to what extent neuroblast migration occurs in the adult human, if at all, based on the rarity of immature neuron marker doublecortin (DCX) expressing neurons along the RMS (Sanai et al., 2011), while Curtis et al. (2007) report neurogenesis to occur in a fully functional RMS even in adulthood. Recently, Ernst et al. (2014) reported that neuroblast migration to the OB may be diminished in adulthood in the human brain but proposed that neuroblasts could migrate to the striatum. Indeed, levels of DCX in the striatum were similar to those found in the DG and SVZ, a feature not exhibited in rodents (Ernst et al., 2014). Also DCX+ neurons with migratory morphology are present in the white matter below the prefrontal cortex of postnatal non-human primates and humans (Fung et al., 2011). The marked inter-species differences between rodent and human neurogenesis highlight the need to study neurogenesis in the adult human brain to understand the unique features of this process in humans.Maintenance of Neurogenesis by the Local Neurogenic NicheClusters of different cell types comprise and enclose the SVZ, including astrocytes, endothelia, the vasculature, microglia and ependymal cells. Collectively, they form a microenvironment, or neurogenic niche, serving important roles in maintaining structural integrity and supporting neurogenesis. It is thought that proteins produced locally, or transported to the niche regulate neurogenesis. The role of astrocytes, ependymal cells, the vasculature and their associated proteins in regulating neurogenesis will be discussed below.AstrocytesAstrocytes are involved in fate specification and promote proliferation of NSCs. In the absence of astrocytes, DG NSCs in rodents tend towards glial fates (Song et al., 2002). Similarly, Lim and Alvarez-Buylla (1999) found that astrocytes promote proliferation of Type A neuroblasts from Type B/C cells in vitro. Although secreted factors were hypothesised to mediate this effect, astrocyte cultured medium alone did not induce neuroblast proliferation. The authors concluded that glia-derived soluble factors may be necessary, but are not sufficient for neuroblast proliferation, so cell-cell contact involving cell surface receptors or membrane bound proteins may be required.Interestingly, astrocytes transplanted from the adult rat spinal cord to neurogenic regions did not induce neurogenesis (Song et al., 2002). This could be due to the distinct gene expression profiles of astrocytes from different regions. Barkho et al. (2006) characterised neurogenesis-promoting and neurogenesis-inhibiting astrocytes in rat brains and showed that secreted factors highly expressed in hippocampal and SVZ astrocytes, such as transforming growth factor β (TGF-β), IL-1β and IL-6 promoted neuronal differentiation, whereas factors highly expressed in adult spinal cord astrocytes, such as decorin, had an inhibitory effect on neuronal differentiation. Thus, the effect of astrocytes on neurogenesis is a function of both cell-intrinsic properties and the local environment.Ependymal cellsEpendymal cells border the lateral ventricles and interact with CSF. In particular, multiciliated processes on ependymal cells are polarised and generate CSF flow (Sawamoto et al., 2006). A gradient of Slit, a chemorepulsive factor, is also generated alongside the flow of CSF, which directs neuroblasts along the RMS to the OB. Disruption to cilia dissipates this gradient and interferes with neuroblast migration, an effect also noted in Slit mutants (Nguyen Ba-Charvet et al., 2004). Additionally, astrocytes become disorganised and invade layer 2, possibly because Slit is expressed by migrating neuroblasts, which act on Robo receptors on astrocytes (Kaneko et al., 2010). Thus neuroblasts modulate their migration by repelling astrocytes through Slit, which is further modulated by the action of ependymal cells controlling the CSF-Slit gradient.Vascular nicheThe SGZ and SVZ are both closely associated with a developed vascular network (Tavazoie et al., 2008; Nie et al., 2010; Sawada et al., 2014), where Type B NSCs and Type C TAPs establish direct contact with capillaries and enable tight control of the local microcirculation by altering capillary diameter and hence bloodflow (Lacar et al., 2012). Tavazoie et al. (2008) found that dividing cells lie adjacent to blood vessels by immunostaining endothelial cells with CD31 and dividing cells with Ki67. This indicates that the vascular niche may play a supportive role in neurogenesis by interacting with the NSC pool. A prime example of this occurs in songbirds, where testosterone induced release of vascular endothelial growth factor (VEGF) stimulates angiogenesis (Louissaint et al., 2002). Angiogenesis is associated with the production of brain derived neurotrophic factor (BDNF) (Leventhal et al., 1999) which in turn triggers neurogenesis (Louissaint et al., 2002). The vascular network also plays an important role as a scaffold for which neuroblasts can migrate to reach the OB (Bovetti et al., 2007; Tavazoie et al., 2008). Blood vessels may also facilitate injury-induced migration of neuroblasts (see Applications of neurogenesis to injury and Repair; Kojima et al., 2010). Thus the vascular network surrounding the SVZ is an effective means of transporting proteins and other soluble factors that can modulate neurogenesis.The neurogenic niche provides an explanation as to why neurogenesis is limited to the SVZ and SGZ. In the SGZ and SVZ, a myriad of cell types alongside proteins, both locally secreted or transported to the niche provide an environment that encourages neurogenesis and neuronal differentiation, whereas ‘non-neurogenic’ regions lack this support. Indeed, transplantation of hippocampal NPCs to the SVZ, and vice versa, generates OB interneurons and granule cells respectively, whereas transplantation to other areas only generates glia (Suhonen et al., 1996). Yet NPCs are found in many diverse brain regions including the spinal cord, striatum and neocortex, and these can be induced towards neuronal fates in vitro (Palmer et al., 1995). This suggests NSC in non-neurogenic regions are ‘dormant’, but in an appropriately conducive chemical environment could exhibit neurogenic behaviour. This is supported by injury models where neurogenesis from NSCs and NPCs is upregulated following ischemic insult (Ohira et al., 2010). Thus, introducing neurochemical factors expressed in the SVZ or SGZ to non-neurogenic regions may also stimulate neurogenesis in those regions (Jin et al., 2003a).Age related changes in the SVZWhile neurogenesis persists in adulthood, neurogenic potential significantly declines with age. Jin et al. (2003a) reported decreases in BrdU labelled cells of 90% and 50% in the DG and SVZ respectively, between 3 month old mice and 20 month old mice. A reduction in DCX-labelled neuroblasts also occurs in both rodents, humans (Sanai et al., 2011; Wang et al., 2011), and non-human primates (Fung et al., 2011) indicating the loss of migratory neuroblasts to the OB with age . This is also reflected in preliminary data from our laboratory (Fung, unpublished) that suggests that gene expression of proliferation and immature neuron markers, Ki67 and DCX respectively, are inversely correlated with age in humans.The decline of neurogenesis in the ageing brain has been linked to structural and cellular changes in the neurogenic niche. Age-related structural changes found in rodents include stenosis of lateral ventricular walls, via the fusion of medial and lateral walls of the lateral ventricle (Shook et al., 2012), which in turn leads to shrinking of the SVZ, ventricular enlargement and thinning of the ependymal monolayer. This effectively reduces the neurogenic area, and may limit the formation of neuroblasts to the anterior dorsal SVZ (Luo et al., 2006). However, this may not apply to primates, since neurogenesis is thought to occur in the ventral aspect of the lateral ventricle, unlike rodents (Fung et al., 2011).Age-related cellular changes include a reduced pool size of proliferative NSCs and neuroblasts. This reduction is uniformly distributed along the SVZ, apart from the site of fusion, where no NSCs can be found (Shook et al., 2012). Despite a reduced NSC pool size, the percentage of actively mitotic NSCs has been found to increase in rodents with age (Shook et al., 2012). However, this is accompanied by a 1.5 fold increase in the number of cells exiting the cell cycle, as indexed by an increase in BrdU+/Ki67- cells compared to BrdU+/Ki67+ cells (Luo et al., 2006). Elevated caspase 3 activity indicates cell death is also involved in reducing NSC and NPC pools, as well as numbers of migratory neuroblasts, but only in elderly mice aged over 19 months (Luo et al., 2006).Overall, the available data suggest that age-related structural and cellular changes in the SVZ contribute to a reduced capacity for neurogenesis with age due to a decline in NSC pool size and increased cellular senescence. While these age-related changes in the SVZ have been confirmed in rodents, these changes may not necessarily be features of human neurogenesis. Therefore, further investigation must be conducted into age related changes in the SVZ and their effects on human neurogenesis.Regulation of Neurogenesis in the Adult BrainThe available data suggests that the rate of neurogenesis is not fixed but may be modulated in adult life through cell-intrinsic transcription factors or extrinsic mechanisms involving growth factors, morphogens, experience and injury. This section focuses on transcription factor and growth factor regulation of neurogenesis and potential applications of NSC therapy in injury and repair.Intrinsic regulation through transcription factorsA set of transcriptional programs are activated that direct actions and fates of cells in the SVZ (Hsieh, 2012). Specific transcription factors are expressed transiently during each stage of neurogenesis (Figure 3). In early stages, Sox2 influences the proliferation of TAPs, and loss of Sox2 leads to a reduction in proliferating progenitors and number of DCX+ neuroblasts (Ferri et al., 2004). In addition, FoxO3 and TLX are also expressed in NSCs and are involved in their proliferation and maintenance. FoxO3-/- mutants have depleted NSC pools, indicating that FoxO3 is required for NSC self-renewal, presumably through inhibition of the Wnt pathway (Paik et al., 2009). Later stages of neurogenesis involve Pax6, required to promote neurogenesis (Sansom et al., 2009) in place of self-renewal, but inhibits interneuron lineage, generating pyramidal neurons. Finally, a combination of NeuroD1, T-box brain gene 1 and 2 are involved in generating neuronal phenotypes of the OB (Roybon et al., 2009). In particular, Mash1 and neurogenin positive cells, as well as Gsh2 positive cells generate OB interneurons, whereas Olig2 controls neuronal versus oligodendrocyte differentiation. The proportion of cells expressing nestin, Sox2 and Gsh2 are reduced with age. Gene expression of these markers are also reduced in NSCs of aged rodents (Ahlenius et al., 2009), but their expression in humans across age remains to be elucidated.Figure 3: Time course of neurogenesis is dictated by transcriptional control (Hsieh, 2012). Neurogenesis involves distinct stages of NSC proliferation, fate specification, differentiation, survival and maturation (top panel), where Type B1 and B2 NSCs cycle into TAPs, which produce neuroblasts that migrate and mature into functional neurons. Associated with each stage is the expression of a specific set of transcription factors that regulate neurogenesis (bottom panel).Extrinsic regulation through growth factorsGrowth factors offer an extrinsic approach to affect cell programming and may have differential effects depending on the factor. They are involved in promoting normal development and maturation of the central nervous system (Abe et al., 2000), but also serve important neurogenic functions. In rodent models, fibroblast growth factor-2 (FGF-2) increases the number of newborn neurons reaching the OB, whereas epidermal growth factor (EGF) enhances astrocyte formation (Kuhn et al., 1997). The number of BrdU+ cells can be enhanced in the both the DG and SVZ, following administration of FGF-2 or heparin-binding epidermal growth factor, HB-EGF (Jin et al., 2003a). This effect is more pronounced in aged rodents (20 months), and restores SVZ BrdU+ cells to levels comparable to untreated young 3-month rodents. In addition, BrdU+ cells colocalised with DCX (Jin et al., 2003a), demonstrating that age related declines in neurogenesis can countered by exogenous application of growth factors .Other growth factors of interest include glial derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF). GDNF acts as a chemoattractant, stimulating neuroblast migration to the OB (Paratcha et al., 2006). In the adult monkey, TrkB receptors are expressed in NPCs (Tonchev et al., 2007) and the actions of BDNF on these receptors mediate the survival of migratory neuroblasts (Bath et al., 2008). BDNF is known to have varied effects on proliferation and differentiation (Bath et al., 2012) and may also act on the p75 receptor to stimulate neuroblast production and their migration in vitro (Young et al., 2007).Given the importance of growth factors in regulating neurogenesis, it is likely that gene expression and protein levels of BDNF and other growth factors and their receptors decline with age in the human brain, contributing to reduced neurogenesis. Evidence from animal models indicate that changes in growth factor and receptor expression across age correlates with neurogenesis. In the rat hippocampus, levels of FGF-2, insulin-like growth factor (IGF-1) and VEGF decline with age (Shetty et al., 2005). Olfactory neurogenesis and fine olfactory discrimination is reduced in 24 month old mice compared with 2 month old mice, and this is correlated with a reduced expression of EGFR (Enwere et al., 2004). Moreover, EGF infusion produces a smaller proportion of new neurons in old mice compared to young mice, which could be linked to the reduced expression of EGFR. A similar reduction in olfactory neurogenesis and olfactory discrimination can be observed in mutant mice with reduced or null expression of TGF-α (Enwere et al., 2004; Tropepe et al., 1997), which is the primary ligand of EGFR in the brain (Seroogy et al., 1993; Weickert and Blum, 1995). How levels of these growth factors and their expression change with age in the adult human is unknown and is the primary subject of this investigation.Applications of neurogenesis to injury and repairAlthough the injured central nervous system undergoes repair sparingly, NSC therapy is a possible treatment option, based on a large number of studies that indicate neurogenesis is upregulated following ischemic insult (reviewed in Ohira et al., 2011). SVZ-derived neuroblasts are able to migrate away from their usual route into regions adjacent to the infarct, regulated in part by a gradient of the chemokine stromal cell derived factor-1α (SDF-1α) interacting with its receptor, CXCR4 (Thored et al., 2006; Robin et al., 2006), before differentiating accordingly to replace damaged neurons. This has been observed in the striatum following a middle cerebral artery occlusion (Arvidsson et al., 2002; Jin et al., 2003b), where BrdU+/NeuN+ labelling is increased 31-fold four weeks post-injury (Arvidsson et al., 2002). Progenitors are also present in the human SVZ post-ischemia (Macas et al., 2006). In the rodent neocortex, no evidence of SVZ neuroblast migration has been found, but endogenous NPCs in layer 1 can proliferate freely to form cortical interneurons, which integrate into existing circuitry (Ohira et al., 2010; Magavi et al., 2000).As in the healthy brain, neurogenesis can be increased after injury through growth factor infusion. In the DG, FGF-2 knockout mice produce fewer neurons post-injury compared to wild type homozygotes, but this can be rescued by overexpression of FGF-2 through injections of FGF-2 encoding viral vectors (Yoshimura et al., 2003). Increases in neurogenesis have been demonstrated using EGF (Ninomiya et al., 2006) acting on EGFR+ TAPs derived from the SVZ. Neuroblast formation is then induced in place of TAP proliferation by discontinuation of EGF. Similar findings have been reported by Tureyen et al. (2005) using EGF and FGF-2 in combination.The ability for the NSCs to be produced after injury to replace neurons in normally non-neurogenic regions and their possible augmentation through growth factors presents a positive starting point for developing NSC therapy. There are still many questions relating to whether this regenerative capacity is retained throughout age in the adult human brain. One approach towards answering these questions is to investigate whether the expression of growth factors thought to regulate neurogenesis in the SVZ are altered with age. Recently, Werry et al. 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