Picano et al. BMC Cancer 2012, 12:157 http://www.biomedcentral.com/1471-2407/12/157 damage – the result of age-associated alteration in large arteries and the progressive mismatch of their cross-talk with small cerebral arteries – a potent risk factor for cognitive decline and the onset of dementia in older individuals [57]. Morphological and functional altera- tions of the dermal microcirculation identified by capil- lary microscopy have been identified in 145 physicians exposed to low-dose ionizing radiation (radiologists, car- diologists and orthopaedic specialists) compared to 105 non-exposed controls [58]. The combination of macro- and micro-vascular damage can thus, in principle, exert negative effects on the neurovascular and neurocognitive function of subjects exposed to ionized radiation. Neurocognitive effects: direct radiation effects on neural cells Terminally differentiated neurons have reduced or proliferative capacity, so they have not been traditionally regarded as critical radiation targets. However, tissue tol- erance of the normal brain to radiation therapy is very limited and radiation doses have to be tailored to minimize the deleterious effects on the nervous system [59]. Of special interest, cognitive decline in patients with radiological abnormalities (white matter hyperinten- sities and global cortical atrophy) was associated with radiotherapy doses that are considered safe (< 2 Sv) [60]. There are four possible cellular targets of radiation dam- age: endothelial cells, which are sensitive to radiation damage although they may recover after initial reduction in cell number [61]; oligodendroglial stem cells, which represent 75% of the cycling cells in the human brain and are permanently destroyed after high-dose radiation with subsequent delayed demyelinization [62]; microglial cells, which are mature cells that continue to divide in the CNS and are decreased in the spinal cord of irra- diated rats [63]; neural stem cells giving rise to adult- born neurons [64]. At present there is consensus that adult neurogenesis occurs in two main areas (Figure 4) of the human brain: the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, where new granule generated neurons have been associated with learning/memory and mood modulation, and the sub- ventricular zone (SVZ), from which newborn cells mi- grate through the rostral migratory stream and give rise to newly generated neurons in the olfactory bulb [65,66]. Adult neural stem cells are highly sensitive to radiation even at chronic, moderate doses [67-70]. For example, with a cumulative dose of 0.5 Sv, in a mouse model, re- petitive exposure more closely mirroring the model of professional exposure had a much more pronounced ef- fect on cellular neurogenesis than acute exposure [70]. Reduction/arrest of adult neurogenesis in the hippocampus by low targeted X-irradiation impairs cognitive tests related to hippocampal memory [71,72]. Acute irradiation with Page 7 of 13 sublethal dose causes reduction of cell proliferation and morphological alterations in the olfactory bulb with succes- sive development of gliosis [73]. Interestingly, focal SVZ ir- radiation reduced the proliferation rate of newly generated olfactory neurons, thus resulting in long-term olfactory memory dysfunction; these data suggest that newborn adult neurons are involved in the memory of olfactory traces [74]. Previous studies suggested that radiation exposure might represent a risk for schizophrenia in humans [75,76]. In 10,834 individuals irradiated in childhood for tinea capitis (mean dose = 1.5 Gy), no association was found between ra- diation exposure and risk of schizophrenia, although for the subgroup irradiated at < 5 years of age a trend was found (hazard ratio = 1.18, 95% CI = 0.96–1.44, p = 0.1) [75]. Re- cent data showed that rats exposed to fractionated radiation dose present reduction of neurogenesis in DG and SVZ associated with schizophrenia-like behavior [77]. Finally, it should be remarked that neural stem cells and microglial cells can be impaired several years before clinically overt neurodegenerative diseases such as sporadic Alzheimer’s and Parkinson’s disease [66,78]. At a molecular level, the major fundamental mechanism triggered in the irradiated brain and responsible for structural alterations is DNA damage followed by pro-oxidant, pro-inflammatory and enhanced apoptotic response [79]. These effects have all been described in circulating lymphocytes and plasma of interventional cardiologists [80,81]. In the brain, apoptosis of neuronal stem cells and reduction of their proliferation rate following irradiation has been repeatedly associated with cognitive deficits in adult mammals [70-73]. However, the molecular substrate of cognitive impairment following low-dose radiation is still debated; in particular, the question of when and to what extent synaptic transmission/plasticity is affected by fractionated radiation is by and large un- answered. Previous results showed that hippocampal slices undergo changes in neuronal excitability following moder- ate doses of ionizing radiation [82]. More recently, in the mouse brain, Silasi et al. [70] reported perturbations in cell signaling associated with impairment of hippocampal neurogenesis. This issue is becoming even more relevant following recent observations by Mancuso et al. [25] on changes occurring in unexposed regions neighboring damaged cells, due to cell-to-cell communication or soluble factors released by irradiated cells. Thus, an accurate inves- tigation of fractionated vs acute radiation damage to neur- onal/neural cells in different brain areas is needed in order to understand the link between molecular mechanisms of radiation-induced alterations and cognitive impairment. This represents an important topic, since outside the field of radiation therapy [83], the evidence linking radiation ex- posure to cognitive disorders is weak, especially in the case of occupationally exposed medical workers [76,78]. Yamada et al. reported no relationship between radiation exposure (< 4 Gy) and dementia in 2,286 aging atomic bomb