Effects of hemochromatosis and transferrin gene mutations on peripheral iron dyshomeostasis in mild cognitive impairment and Alzheimer's and Parkinson's diseases.

Deregulation of iron metabolism has been observed in patients with neurodegenerative diseases. We have carried out a molecular analysis investigating the interaction between iron specific gene variants [transferrin (TF, P589S), hemochromatosis (HFE) C282Y and (H63D)], iron biochemical variables [iron, Tf, ceruloplasmin (Cp), Cp:Tf ratio and % of Tf saturation (% Tf-sat)] and apolipoprotein E (APOE) gene variants in 139 Alzheimer's disease (AD), 27 Mild Cognitive Impairment (MCI), 78 Parkinson's disease (PD) patients and 139 healthy controls to investigate mechanisms of iron regulation or toxicity. No difference in genetic variant distributions between patients and controls was found in our Italian sample, but the stratification for the APOEε4 allele revealed that among the APOEε4 carriers was higher the frequency of those carriers of at least a mutated TF P589S allele. Decreased Tf in both AD and MCI and increased Cp:Tf ratio in AD vs. controls were detected. A multinomial logistic regression model revealed that increased iron and Cp:Tf ratio and being man instead of woman increased the risk of having PD, that increased values of Cp:Tf ratio corresponded to a 4-fold increase of the relative risk of having MCI, while higher Cp levels were protective for PD and MCI. Our study has some limitations: the small size of the samples, one ethnic group considered, the rarity of some alleles which prevent the statistical power of some genetic analysis. Even though they need confirmation in larger cohorts, our data suggest the hypothesis that deregulation of iron metabolism, in addition to other factors, has some effect on the PD disease risk.

Movement-induced uncoupling of primary sensory and motor areas in focal task-specific hand dystonia.

INTRODUCTION: Due to growing evidence of sensorimotor integration impairment in focal task-specific hand dystonia, we aimed at describing primary sensory (S1) and primary motor (M1) cortex source activities and their functional cross-talk during a non-dystonia-inducing sensorimotor task free of biases generated by the interfering with the occurrence of dystonic movements. METHOD: Magnetoencephalographic brain signals and opponens pollicis (OP) electromyographic activities were acquired at rest and during a simple isometric contraction performed either alone or in combination with median nerve stimulation. The task was performed separately with the right and left hand by eight patients suffering from focal task-specific hand dystonia and by eight healthy volunteers. Through an ad hoc procedure Functional Source Separation (FSS), distinct sources were identified in S1 (FSS1) and M1 (FSM1) devoted to hand control. Spectral properties and functional coupling (coherence) between the two sources were assessed in alpha [8,13]Hz, beta [14,32]Hz and gamma [33,45]Hz frequency bands. RESULTS: No differences were found between spectral properties of patients and controls for either FSM1 or FSS1 cerebral sources. Functional coupling between FSM1 and FSS1 (gamma band coherence), while comparable between dystonic patients and healthy controls at rest, was selectively reduced in patients during movement. All findings were present in both hemispheres. DISCUSSION: Because previous literature has shown that gamma-band sensory-motor synchronization reflects an efficiency index of sensory-motor integration, our data demonstrate that, in dystonic patients, uncoupling replaces the functional coupling required for efficient sensory-motor control during motor exertion. The presence of bi-hemispheric abnormalities in unilateral hand dystonia supports the presence of an endophenotypic trait.

An unusual cause of dementia: essential diagnostic elements of corticobasal degeneration-a case report and review of the literature.

Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease.

Implications of metal exposure and liver function in Parkinsonian patients resident in the vicinities of ferroalloy plants.

Valcamonica is an Italian valley where ferro-manganese industries have been active for a century and where an increased prevalence of parkinsonism was observed. A group of 93 patients (65 from Valcamonica, 28 from the reference area of Brescia city) and 76 controls (52 from Valcamonica, 24 from Brescia) were screened for serum Cu, Zn, Fe, Mn in blood (MnB) and urine (MnU), transferrin, peroxides, alanine (ALT) and aspartate (AST) transaminases and direct bilirubin. Test results were compared among groups according to the residential area and related to the disease severity. Valcamonica patients had a serum-increase of Cu, as well as of AST/ALT ratio, and a serum-decrease of Zn and Fe compared with other subgroups of cases and controls. Cases and controls from Valcamonica had higher MnB and MnU levels compared to cases and controls from Brescia. After controlling for the duration of illness, the Unified Parkinson's Disease Rating Scale III domain correlated with serum Cu and AST/ALT ratio. Our results suggest the possibility that, in this area, a lifetime exposure to neurotoxicants and to Mn in particular, when accompanied to a subclinical liver dysfunction, may pose an increased risk for neurodegenerative disorders via metal metabolism (Cu, Zn, Fe) abnormalities.

High frequency repetitive transcranial magnetic stimulation decreases cerebral vasomotor reactivity.

OBJECTIVE: Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently employed as a therapeutic strategy for stroke, although its effects on cerebral hemodynamics has been poorly investigated. This study aims to examine the impact of high frequency rTMS on cerebral vasomotor reactivity (VMR). METHODS: Twenty-nine healthy subjects were randomly assigned to real (19) or sham 17-Hz rTMS, applied on primary motor cortex (M1) of the dominant hemisphere. All subjects underwent Transcranial Doppler of the middle cerebral arteries to evaluate mean flow velocity and VMR before (T(0)) and within 10 min (T(1)) following rTMS. Four subjects underwent further VMR evaluations at 2 (T(2)), 5 (T(3)) and 24 h (T(4)) after rTMS. As a control condition, 10 subjects underwent real (5) or sham rTMS on calcarine cortex. In addition, five acute stroke patients underwent five daily rTMS sessions on the affected hemisphere mimicking a therapeutic trial. RESULTS: Following real rTMS on M1 (p=0.002) and calcarine cortex (p<0.001) VMR decreased with respect to T(0) in both hemispheres, while no change was observed after sham rTMS (p>0.6). VMR tended to remain lower than T(0) until T(3.) Cerebral VMR decreased independently of the stimulated side also in the patients' group. CONCLUSIONS: High frequency rTMS reduces cerebral VMR, possibly as a secondary effect on autonomic control of cerebral hemodynamics. SIGNIFICANCE: The effect of rTMS on cerebral hemodynamics should be carefully considered before proceeding toward a therapeutic application in stroke patients.

Sensorimotor integration in focal task-specific hand dystonia: a magnetoencephalographic assessment.

To obtain a direct sensorimotor integration assessment in primary hand cortical areas (M1) of patients suffering from focal task-specific hand dystonia, magnetoencephalographic (MEG) and opponens pollicis electromyographic (EMG) activities were acquired during a motor task expressly chosen not to induce dystonic movements in our patients, to disentangle abnormalities indicating a possible substrate on which dystonia develops. A simple isometric contraction was performed either alone or in combination with median nerve stimulation, i.e. when a non-physiological sensory inflow was overlapping with the physiological feedback. As control condition, median nerve stimulation was also performed at rest. The task was performed bilaterally both in eight patients and in 16 healthy volunteers. In comparison with results in controls we found that in dystonic patients: i) MEG-EMG coherence was higher; ii) it reduced much less during galvanic stimulation in the hemisphere contralateral to the dystonic arm, simultaneously with iii) stronger inhibition of the sensory areas responsiveness due to movement; iv) the cortical component including contributions from sensory inhibitory and motor structures was reduced and v) much more inhibited during movement. It is documented that a simultaneous cortico-muscular coherence increase occurs in presence of a reduced M1 responsiveness to the inflow from the sensory regions. This could indicate an unbalance of the fronto-parietal functional impact on M1, with a weakening of the parietal components. Concurrently, signs of a less differentiated sensory hand representation--possibly due to impaired inhibitory mechanisms efficiency--and signs of a reduced repertoire of voluntary motor control strategies were found.

Neuroimaging experimental studies on brain plasticity in recovery from stroke.

Topographical cortical organization of sensorimotor area has been shown to be highly plastic, altering his configuration in response to training in different tasks in healthy controls and neurological patients. The term ''brain plasticity'' encompasses all possible mechanisms of neuronal reorganization: recruitment of pathways that are functionally homologous to, but anatomically distinct from, the damaged ones (eg, non-pyramidal corticospinal pathways), synaptogenesis, dendritic arborisation and reinforcement of existing but functionally silent synaptic connections (particularly at the periphery of core lesion). The study of neuroplasticity has clearly shown the ability of the developing brain--and of the adult and ageing brain--to be shaped by environmental inputs both under normal conditions (ie, learning) and after a lesion. Neuronal aggregates adjacent, or distant to a lesion in the sensorimotor area can progressively adopt the function of the injured area. Imaging studies indicate that recovery of motor function after a lesion (i.e. stroke) is associated with a progressive change of activation patterns in specific brain structures. Transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) can detect reshaping of sensorimotor areas; they have a high temporal resolution but have several limitations. TMS can only provide bidimensional scalp maps and MEG depicts three-dimensional spatial characteristics of virtual neural generators obtained by use of a mathematical model of the head and brain. However, the use of objective methods that assess brain reactivity to a physical stimulus (i.e., TMS) or to a sensory input (ie, electrical stimulation to hand and fingers) can integrate information from self-paced motor tasks, because the resolution of abnormal activation over time could be secondary to recovery. Functional MRI (fMRI) and positron emission tomography (PET), on their own, have insufficient time resolution to follow the hierarchical activation of relays within a neural network; however, because of their excellent spatial resolution, they can integrate the findings of TMS and MEG. An integrated approach constitutes, at present, the best way to assess the brain plasticity both under normal conditions and after a lesion.

Sensory-motor interaction in primary hand cortical areas: a magnetoencephalography assessment.

Movement control requires continuous and reciprocal exchange of information between activities of motor areas involved in the task program execution and those elaborating proprioceptive sensory information. Our aim was to investigate the sensorimotor interactions in the region dedicated to hand control in healthy humans, focusing onto primary sensory and motor cortices, by selecting the time window at very early latencies. Through magnetoencephalographic recordings, we obtained a simultaneous assessment of sensory cortex activity modulation due to movement and of motor cortex activity modulation due to sensory stimulation, by eliciting a galvanic stimulation to the nerve (the median nerve) innervating a muscle (the opponens pollicis), at rest or during voluntary contraction. The primary sensory and motor cortices activities were investigated respectively through excitability in response to sensory stimulation and the cortico-muscular coherence. The task was performed bilaterally. A clear reduction of the cortico-muscular coherence was found in the short time window following stimuli (between around 150-450 ms). In the same time period, the motor control of isometric contraction was preserved. This could suggest that cortical component of voluntary movement control was transiently mediated by neuronal firing rate tuning more than by cortico-muscular synchronization. In addition to the known primary sensory cortex inhibition due to movement, a more evident reduction was found for the component known to include a contribution from primary motor areas. Gating effects were lower in the dominant left hemisphere, suggesting that sensorimotor areas dominant for hand control benefit of narrowing down gating effects.

Enhanced APOE2 transmission rates in families with autistic probands.

We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children.