A mathematical model for the evaluation of iron transport across the blood-cerebrospinal fluid barrier in neurodegenerative diseases.

Iron plays important roles in healthy brain but altered homeostasis and concentration have been correlated to aging and neurodegenerative diseases. Iron enters the central nervous system by crossing the brain barrier systems: the Blood- Brain Barrier separating blood and brain and the Blood-Cerebrospinal Fluid Barrier (BCSFB) between blood and CSF, which is in contact with the brain by far less selective barriers. Herein, we develop a two-compartmental model for the BCSFB, based on first-order ordinary differential equations, performing numerical simulations and sensitivity analysis. Furthermore, as input parameters of the model, experimental data from patients affected by Alzheimer's disease, frontotemporal dementia, mild cognitive impairment and matched neurological controls were used, with the aim of investigating the differences between physiological and pathological conditions in the regulation of iron passage between blood and CSF which can be possibly targeted by therapy.

A novel neurocognitive approach for placebo analgesia in neurocognitive disorders.

Neural correlates of placebo analgesia (PA) in patients with neurocognitive disorders have not yet been elucidated. The present study aimed to evaluate how and to what extent executive (dys)functions of the medial prefrontal cortex (MPFC) may be related to PA. To this end, twenty-three subjects complaining of different cognitive deficits (from mild cognitive impairment likely due to Alzheimer's disease to mild AD) were recruited. PA was investigated by a well-known experimental venipuncture pain paradigm (open versus hidden [O-H] application of lidocaine). Patients also underwent a comprehensive neuropsychological evaluation and a functional magnetic resonance imaging (fMRI) GO/No-GO task for eliciting selective activation of the MPFC. Selected neuropsychological variables were correlated to the OH-PA paradigm. The association between the fMRI response on the "No-GO" versus "GO" contrast and PA was investigated over the whole-brain by regression analysis. We showed the existence of a relationship between a lower PA and MPFC dysfunctions through the neuropsychological and fMRI assessment. A separate voxel-based morphometry (VBM) analysis controlled for possible influence of grey matter (GM) volume reduction on both fMRI results and PA. fMRI results were not directly affected by, and therefore independent of, disease-specific GM atrophy, which was indeed located more anteriorly within the rostral anterior cingulate and inversely correlated with PA. Our findings shed new light on the underestimated contribution of executive (dys)functions mediated by the MPFC (response-inhibition, self-monitoring and set-shifting abilities) in PA pathogenesis, with a special purely (i.e. independently from brain structural alterations) functional role played by the MCC. Results are discussed in terms of possible clinical relevance in the management of patients with neurocognitive disorders.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

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.

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.

DCUN1D1 is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is considered as a proteinopathy; therefore, it is conceivable that genes encoding for factors involved in protein misfolding and/or degradation could play a role in its pathogenesis. METHODS: An association study of defective in cullin neddylation 1 (DCN-1)-domain containing 1 (DCUN1D1), which is involved in protein degradation, was carried out in a population of 220 patients with FTLD as compared with 229 age-matched controls. RESULTS: A statistically significant increased frequency of the GG genotype of the DCUN1D1 rs4859146 single nucleotide polymorphism (SNP) was observed in patients compared with controls (6.9 vs. 1.7%, P = 0.011, adjusted OR: 4.39, 95% CI: 1.40-13.78). Stratifying according to the clinical syndrome, significant differences were observed between the behavioral variant of frontotemporal dementia and controls (GG frequency: 6.3 vs. 1.7%, P = 0.02, OR:4.0, 95%, CI = 1.24-12.92), as well as between patients with progressive aphasia compared with controls (15.4 vs. 1.7%, P = 0.014, OR = 11.30, 95%, CI = 1.63-78.45), but not in patients with SD versus controls (8.3 vs. 1.7%, P = 0.18, OR = 5.24, 95% C.I. = 0.45-60.63). No significant differences in allelic and genotypic frequencies of the DCUN1D1 rs4859147 SNP were found. CONCLUSIONS: The GG genotype of the DCUN1D1 rs4859147 SNP represents a risk factor for the development of FTLD, increasing the risk of about fourfold.

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.

The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND AIMS: Neuronal nitric oxide synthase (NOS)1 C276T polymorphism was shown to increase the risk for frontotemporal lobar degeneration (FTLD). In the brain, both NOS1 and NOS3 (endothelial isoform) have been detected. The distribution of NOS3 G894T (Glu298Asp) and T-786C single nucleotide polymorphisms (SNPs) was analyzed in a population of 222 patients with FTLD compared with 218 age-matched controls to determine whether they could influence the susceptibility to develop the disease. RESULTS: A statistically significant increased frequency of the NOS3 G894T SNP was observed in patients as compared with controls (40.0 vs. 31.4%, P = 0.011, OR: 1.65, CI: 1.13-2.42). Conversely, the distribution of the T-786C SNP was similar in patients and controls. No differences were observed stratifying according to gender. DISCUSSION: The NOS3 G894T polymorphism likely acts as risk factor for sporadic FTLD, but studies in larger populations are needed to confirm these preliminary findings.

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.

Haemochromatosis gene (HFE) polymorphisms and migraine: an association study.

Several studies have suggested that iron metabolism may be involved in the pathogenesis of migraine. Using a case-control design, we performed an association study in a cohort of Italian migraine patients to evaluate whether a particular allele or genotype of the haemochromatosis gene (HFE) would modify the occurrence and clinical features of the disease. We genotyped 256 migraine patients and 237 healthy age-, sex- and ethnicity-matched controls for the C282Y and H63D polymorphisms of the HFE gene. Phenotype and allele frequencies of both polymorphisms were similarly distributed in migraine patients and controls. The patients carrying the DD genotype of the H63D polymorphism showed a later age at onset of the disease and an increased number of migraine attacks. Our data suggest that the HFE gene is not a major disease gene for migraine. However, the H63D polymorphism of the HFE gene may be considered a modifying genetic factor in migraine.

Lack of association between the 3092 T-->C Clock gene polymorphism and cluster headache.

Recent studies suggested that genetic factors play a role in cluster headache (CH). However, the type and the number of genes involved in the disease are still unclear. We performed an association study in a cohort of Italian CH patients to evaluate whether a particular allele or genotype of the Clock gene would modify the occurrence and the clinical features of the disease. One hundred and seven CH patients, diagnosed according to the International Classification of Headache Disorders, 2nd Edition, (ICHD-II) criteria, and 210 healthy age, sex and ethnicity-matched controls were genotyped for the 3092 T-->C Clock gene polymorphism (also known as 3111 T-->C). Phenotype and allele frequencies were similarly distributed in CH patients and controls. The clinical features of the disease were not significantly influenced by different genotypes. In conclusion, our study suggests that the 3092 T-->C polymorphism of the Clock gene is unlikely to play an important role in cluster headache.

Insulin sensitivity is impaired in patients with migraine.

Several studies have shown the presence of a comorbidity between migraine and vascular diseases, like hypertension and stroke. The mechanisms of this comorbidity are unknown. Impaired insulin sensitivity has recently emerged as a risk factor for hypertension and stroke. We evaluated insulin sensitivity in 30 young, nonobese, nondiabetic, normotensive migraine patients and in 15 healthy controls. During the OGTT, glucose plasma concentrations were significantly higher in migraineurs than in controls. Insulin sensitivity, as measured by ISI-stumvoll and OGIS-180 indexes, was significantly altered in migraine. Our data show that insulin sensitivity is impaired in migraine and suggest a role for insulin resistance in the comorbidity between migraine and vascular diseases.