Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy.

BACKGROUND: Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest. OBJECTIVE: Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain. METHODS: Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry. RESULTS: The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APPα and brevican levels. CONCLUSION: To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.

Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation.

Radiotherapy is an effective tool in the treatment of pediatric malignancies but it is associated with adverse side effects, both short- and long-term. One common long-term side effect after cranial radiotherapy is cognitive impairment and this is, at least partly, thought to be caused by reduced hippocampal neurogenesis. Neuroinflammation and a perturbed microenvironment are thought to be important in the dysregulation of neurogenesis seen after irradiation (IR). We investigated the effects of a pre-existing, lipopolysaccharide (LPS)-induced systemic inflammation at the time of IR in both males and females. A single dose of 8 Gy to the brain of postnatal day 14 mice caused an upregulation of cytokines/chemokines (IL-1ß, MIP-1ß, IL-12, GM-CSF, MIP-1α, IL-17, CCL2 and KC) 6 h after IR, more so in females. Caspase-3 activity, reflecting apoptosis and possibly microglia activation, was elevated 6 h after IR. Females treated with LPS before IR showed a higher caspase-3 activity compared with males. During the chronic phase (3 months post IR), we found that LPS-induced inflammation at the time of IR aggravated the IR-induced injury in both male and female mice, as judged by reduced bromodeoxyuridine incorporation and neurogenesis (doublecortin-positive cells) in the hippocampus. At this late time point, the microglia density was increased by IR, more so in females, indicating long-term effects on the microenvironment. IR increased anxiety-related behavior in vehicle-, but not LPS-, treated animals. However, exploratory behavior was affected by IR in both vehicle- and LPS-treated mice. In conclusion, we found that LPS administration before IR of the young mouse brain aggravated the injury, as judged by reduced hippocampal neurogenesis. This supports the clinical practice to postpone radiotherapy if the patient shows signs of infection. Systemic inflammation is not always obvious, though, for example because of concurrent corticosteroid treatment, so careful monitoring of inflammation is warranted.

Irradiation to the young mouse brain impaired white matter growth more in females than in males.

Modern therapy cures 80% of all children with brains tumors, but may also cause long-lasting side effects, so called late effects. Radiotherapy is particularly prone to cause severe late effects, such as intellectual impairment. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender, where girls suffer more severe late effects than boys. The reason for this difference between boys and girls is unknown, but very few experimental studies have addressed this issue. Our aim was to investigate the effects of ionizing radiation on the corpus callosum (CC) in both male and female mice. We found that a single dose of 8 Gray (Gy) to the brains of postnatal day 14 mice induced apoptosis in the CC and reduced the number of proliferating cells by one third, as judged by the number of phospho-histone H3 positive cells 6 h after irradiation (IR). BrdU incorporation was reduced (62% and 42% lower in females and males, respectively) and the number of oligodendrocytes (Olig2(+) cells) was lower (43% and 21% fewer in females and males, respectively) 4 months after IR, so the lack of developing and differentiated cells was more pronounced in females. The number of microglia was unchanged in females but increased in males at this late time point. The density of microvessel profiles was unchanged by IR. This single, moderate dose of 8 Gy impaired the brain growth to some extent (8.1% and 0.4% lower brain/body weight ratio in females and males, respectively) but the CC growth was even more impaired (31% and 19% smaller in females and males, respectively) 4 months after IR compared with non-irradiated mice. In conclusion, this is the first study to our knowledge demonstrating that IR to the young rodent brain affects white matter development more in females than in males.

Prevalence of attention deficit disorder, residual type, and other psychiatric disorders in patients with irritable colon syndrome.

On the basis of the observations that chronic nonspecific diarrhea is a precursor of irritable colon syndrome and that chronic nonspecific diarrhea is associated with attention deficit disorder in childhood, the authors conducted a psychiatric diagnostic evaluation of 22 adults with irritable colon syndrome. Six (27%) of the patients received a diagnosis of attention deficit disorder, residual type, six (27%) were diagnosed as having dysthymic disorder, and five (23%) had had episodes of unipolar depression. The relationship between the presence of these disorders and greater severity of irritable colon syndrome was statistically significant.