Chemotherapy-Induced Neurotoxicity: Evidence of a Protective Role of CC Homozygosis in the Interleukin-1ß Gene-511 C>T Polymorphism.

We hypothesized that the IL-1ß-511 C>T polymorphism could be associated with the development of neurotoxicity and that it could be a possible biomarker to rate the risk of occurrence of neurotoxicity in cancer patients. Genomic DNA was extracted from 85 cancer patients: 49 received systemic chemotherapeutic treatment (CHT) and 36 patients did not receive it (No-CHT). All subjects were genotyped for the functionally active polymorphisms of IL-1ß-511 C>T. We estimated neurotoxicity with the evaluation of neurological deficits. CHT patients showed erythrocytopenia, neurological deficit and a slight lowering of cognitive performance. The subgroup of patients carrying the CC genotype of the IL-1ß-511 C>T gene showed lesser neurological deficits. In the context of cancer treatment, we suggested the potential value of IL-1ß-511 C>T as genetic biomarkers to identify patients with higher risk to develop neurological deficits.

Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) frequently affects women of childbearing age. While short-term effects of pregnancy on MS course are well-known, whether pregnancy may influence long-term disability progression is debated. METHODS: A two-centre retrospective study to investigate long-term effect of pregnancy on disability was performed in a population of MS women. Survival analyses and multivariate Cox proportional regression models (including early predictors of MS severity and exposure to disease-modifying treatments) were performed to compare time to reach well-established disability milestones in nulliparous women and in those with pregnancies after MS onset ('parous'). Women with pregnancies before MS onset were excluded from analyses as they represent a heterogeneous group. RESULTS: Data about 445 women (261 nulliparous, 184 'parous') were analysed. A longer time to reach Expanded Disability Status Scale (EDSS) 4.0 and 6.0 was observed in parous women; Cox regression models revealed a lower risk for 'parous' than nulliparous women in reaching EDSS 4.0 and 6.0 (HR = 0.552, p = 0.008 and HR = 0.422, p = 0.012 respectively). CONCLUSION: Our findings suggest that pregnancy after MS onset is associated with a slower long-term disability progression. Whether this represents a biological/immunological effect, or reflects a higher propensity toward childbearing in women with milder disease, it remains uncertain deserving further investigations.

The Neurobiological Basis of the Distress Thermometer: A PET Study in Cancer Patients.

The objective of this study was to investigate the possible associations between the Distress Thermometer (DT) scores and the brain metabolism of structures involved in stress response. Twenty-one cancer patients were assessed using the DT, Problem Checklist and Hospital Anxiety and Depression Scale (HADS). The psychological measures were correlated with [18 F]PET-FDG brain glucose metabolism. Multiple and linear regression and binary logistic regression were run to analyse data. The DT and HADS scores illustrated that 48% of patients were distressed, 19% were depressed and 48% were anxious. Results showed that some subcortical areas activity, such as part of midbrain and of hypothalamus, was correlated with the DT scores. The Problem Checklist scores correlated with the activity of the same areas and included more regions in the limbic forebrain and brainstem. Compared with the DT and Problem Checklist, HADS-Depression scores showed a more extensive pattern of correlation with brain activity, including limbic and cortical areas. The results highlighted that the DT scores correlated with the activity of brain areas typically involved in stress response. Indeed, hypothalamus metabolism was found to be the best predictor of distressed patients.

Age of onset of mood disorders and complexity of personality traits.

Objective. The aim of the present study is to evaluate the link between the age of onset of mood disorders and the complexity of the personality traits. Methods. 209 patients with major depressive or manic/hypomanic episodes were assessed using the Structured Clinical Interview for DSM Axis I diagnoses and the Millon Clinical Multiaxial Inventory-III (MCMI-III). Results. 17.2% of the patients had no elevated MCMI-III scores, 45.9% had one peak, and 36.9% had a complex personality disorder with two or more elevated scores. Mood disorders onset of 29 years or less was the variable most related to the complexity of personality disorders as indicated from a recursive partitioning analysis. Conclusions. The relationship between mood disorders and personality traits differ in reference to age of onset of the mood disorder. In younger patients, maladaptive personality traits can evolve both in a mood disorder onset and in a complex personality disorder, while the later development of a severe mood disorder can increase the personality symptomatology. Our results suggest a threshold of mood disorder onset higher compared to previous studies. Maladaptive personality traits should be assessed not only during adolescence but also in young adults to identify and treat potential severe mood disorders.

The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients.

AIM: A growing number of neuropsychological studies reported that chemotherapy may impair brain functions, inducing persistent cognitive changes in a subset of cancer survivors. The aim of this paper was to investigate the neural basis of the chemotherapy induced neurobehavioral changes by means of metabolic imaging and neuropsychological testing. METHODS: We studied the resting brain [¹8F]FDG-PET/CT images of 50 adult cancer patients with diagnosis of lymphoma: 18 patients were studied prior and 32 after to chemotherapy. All patients underwent to a neuropsychological examination assessing cognitive impairment (tests for shifting attention, verbal memory, phonemic fluency), depression, anxiety and distress. RESULTS: Compared to no chemotherapy patients, the treated group showed significant bilateral lower rate of glucose metabolism in prefrontal cortices, cerebellum, medial cortices and limbic brain areas. The metabolism of these regions negatively correlated with number of cycles and positively with post-chemotherapy time. The treated group showed a poorer performance in many frontal functions, but similar level of depression, anxiety and distress. CONCLUSIONS: Chemotherapy induced significant long-term changes in metabolism of multiple regions with a prevailing involvement of the prefrontal cortex. The observed cognitive dysfunctions could be explained by these changes. The recovery from chemotherapy is probably affected by treatment duration and by the time elapsed after its end. We speculated that the mechanism could be an accelerating ageing / oxidative stress that, in some patients at risk, could result in an early and persistent cognitive impairment.

Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.

OBJECTIVE: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. METHODS: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. RESULTS: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. CONCLUSIONS: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.

A family with autosomal dominant leukodystrophy linked to 5q23.2-q23.3 without lamin B1 mutations.

BACKGROUND AND PURPOSE: Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. METHODS: We carried out a genome-wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, multiplex ligation-dependent probe amplification and Southern blot. RESULTS: We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy-number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. CONCLUSIONS: This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.

Mutations in the lamin B1 gene are not present in multiple sclerosis.

BACKGROUND: Whole gene duplication of the lamin B1 gene (LMNB1), encoding for a protein of the nuclear lamina, causes an adult-onset autosomal dominant leukodystrophy (ADLD). Clinical features of ADLD (onset in adult life, dysautonomic symptoms, followed by pyramidal and cerebellar dysfunctions) partially resemble those of multiple sclerosis (MS), particularly the primary-progressive form. Our aim was to test whether LMNB1 gene mutations were present amongst patients with a diagnosis of MS. METHODS: One hundred eighty-two MS patients were screened for copy number variations of the LMNB1 gene using a qPCR assay. Point mutations in the LMNB1 gene were searched by denaturing high-performance liquid chromatography and direct sequencing in a subgroup of 16 patients with familial MS. RESULTS: No duplication/deletion of the lamin B1 gene was found amongst MS patients, and no point mutation was identified in the familial cases. CONCLUSION: Our work indicates that lamin B1 defects are probably not responsible for signs and symptoms resembling multiple sclerosis.

Investigating the genetic role of aquaporin4 gene in migraine.

Aquaporin4 (AQP4) has an important role in water homeostasis of human brain and a dysfunction of AQP4 could induce pathological conditions in neuronal activity. The purpose of our work was to evaluate the association of polymorphisms in the AQP4 gene with the risk and the clinical features of migraine. A total of 293 migraineurs and 249 controls were involved in the study. They were genotyped for four single nucleotide polymorphisms (SNPs) of AQP4 gene. No significant difference in the distribution of AQP4 genotypic and allelic frequencies between cases and controls was found. In addition, haplotype analysis did not show any significant difference. Comparison of the clinical features of the disease according to different AQP4 genotypes showed no significant difference. Our data do not support the hypothesis that the AQP4 gene could represent a genetic susceptibility factor for migraine.

Reversible MRI abnormalities in a patient with recurrent status migrainosus.

Status migrainosus is a condition characterized by a migraine attack causing disability, with or without aura, lasting for > 72 h. The pathophysiological mechanisms underlying this complication of migraine remain a matter of debate. We describe a migraine without aura patient who presented two episodes of status migrainosus associated with recurrent and reversible brain magnetic resonance imaging abnormalities. These abnormalities, confirmed also by positron emission tomography, suggest that status migrainosus can be associated with a condition of vasogenic cerebral oedema.

Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis.

There are conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene. The C677T polymorphism reduces enzymatic capability by 50% and causes hyperhomocysteinaemia. We performed a meta-analysis of all published studies investigating the association between the MTHFR gene and migraine. Pooled odds ratios (OR) were estimated using random (RE) and fixed effects (FE) models. Among the overall 2961 migraineurs there was no significant difference compared with controls. Only in migraine with aura was the TT genotype associated with a higher risk of disease compared with the CC genotype [FE OR 1.30, 95% confidence interval (CI) 1.06, 1.58; RE OR 1.66, 95% CI 1.06, 2.59]. In the same subgroup a significant difference was observed in the comparison between TT and CT + CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43). This study provides evidence for an association of the MTHFR gene only in migraine with aura.

Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid.

The study set out to investigate the role of corticotrophin-releasing factor (CRF) and orexin-A in chronic migraine (CM) and medication-overuse headache (MOH). Twenty-seven patients affected by CM and 30 with MOH were enrolled. Control CSF specimens were obtained from 20 age-matched subjects who underwent lumbar puncture for diagnostic purposes, and in all of them CSF and blood tests excluded central nervous system or systemic diseases. Orexin-A and CRF were determined by radioimmunoassay methods. Significantly higher levels of orexin-A and CRF were found in the CSF of MOH and to a lesser extent in patients with CM compared with control subjects (orexin-A: P < 0.001 and P < 0.02; CRF: P < 0.002 and P < 0.0003). A significant positive correlation was also found between CSF orexin-A values and those of CRF (R = 0.71; P < 0.0008), monthly drug intake group (R = 0.39; P < 0.03) and scores of a self-completion 10-item instrument to measure dependence upon a variety of substances, the Leeds Dependence Questionnaire (LDQ) in the MOH group (R = 0.68; P < 0.0003). The significantly higher orexin-A levels found in CM and MOH can be interpreted as a compensatory response to chronic head pain or, alternatively, as an expression of hypothalamic response to stress due to chronic pain. A potential role for orexin-A in driving drug seeking in MOH patients through activation of stress pathways in the brain can also be hypothesized.

Interleukin 6 gene polymorphisms are not associated with aneurysmal subarachnoid haemorrhage in an Italian population.

OBJECTIVE: Several lines of evidence indicate a role for inflammatory processes in the development of cerebral aneurysms. Recently, polymorphisms in the promoter region of the interleukin 6 (IL6) gene were shown to be associated with intracranial aneurysmal disease. The purpose of this study was to verify the association of two functionally active polymorphisms (-174 G>C and -572 G>C) in the promoter region of the IL6 gene with the risk and clinical features of aneurysmal subarachnoid haemorrhage (SAH) in an Italian population. METHODS: A total of 179 consecutive aneurysmal SAH patients and 156 healthy controls were involved in the study. Cases and controls were genotyped for the -174 G

The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine.

Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.

Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study.

AIMS AND METHODS: In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. RESULTS: Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57-1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82-1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. CONCLUSION: The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf.

[Helicobacter pylori and headache: a minireview]. / Helicobacter pylori e cefalea essenziale: minireview.

The interest that surrounds the bacterium Helicobacter pylori (H. pylori) is due not only to its causal role in several gastroduodenal diseases, but also to its supposed involvement in the pathogenesis of extragastric manifestations. This review provides a literature update on the hypothetic correlation between H. pylori and headache. The authors examine three aspects of this potential association: epidemiology, intervention trials and pathogenesis. Regarding the first, apart in some subgroups, no difference in prevalence exists between patients and controls. Considering the intervention studies, it is documented that, at 6 and 12 months, bacterial eradication is associated to disappearance of symptoms in 23% and 28% of cases, and to a significant decrease of intensity, frequency and duration of acute attacks in the remaining patients. As to the pathogenetic aspect, if H. pylori has a role, it does not act through oxidative stress. In conclusion, the involvement of H. pylori infection in the pathogenesis of headache is unclear. Further investigations should focalize on particular subgroups of patients and, encouraged from data produced by intervention studies, evaluate the long-term benefit of eradication.