A Compartmental Model for the Iron Trafficking Across the Blood-Brain Barriers in Neurodegenerative Diseases.

Iron accumulation in the brain is supposed to play a central role in the induction of oxidative stress and consequently in neurodegeneration. The sensitive balance of iron in the brain is maintained by the brain barriers system, i.e., the blood-brain barrier between the blood and brain interstitial fluid and the blood-cerebrospinal fluid barrier between the blood and cerebrospinal fluid (CSF). In this work, we proposed a three-compartmental mathematical model simulating iron trafficking between blood, CSF, and cerebral space, describing the direction of fluxes based on the structural and functional characteristics of the brain barriers system. Different techniques of sensitivity analysis were used to evaluate the most important parameters, providing an indication for the most relevant biological functions that potentially affect the physiological transport of iron across brain barriers.

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.

Efficacy of Osteopathic Manipulative Treatment on postural control in Parkinsonian patients with Pisa syndrome: A pilot randomized placebo-controlled trial.

BACKGROUND: Pisa syndrome (PS) is a clinical condition frequently associated with Parkinson's disease (PD). It is characterized by a trunk lateral flexion higher than 10 degrees and reversible when lying. One pathophysiological hypothesis is the altered verticality perception, due to a somatosensory impairment. Osteopathic Manipulative Treatment (OMT) manages fascial-system alterations, linked to somatic dysfunctions. Fascial system showed to be implicated in proprioceptive sensibility. OBJECTIVE: The aim of the study was to assess OMT efficacy on postural control in PD-PS patients by stabilometry. METHODS: In this single-blinded trial we studied 24 PD-PS patients, 12 of whom were randomly assigned to receive a multidisciplinary physical therapy protocol (MIRT) and sham OMT, while the other 12 received four OMT plus MIRT, for one month. The primary endpoint was the eye closed sway area assessment after the intervention. Evaluation of trunk lateral flexion (TLF) with DIERS formetrics was also performed. RESULTS: At one month, the sway area of the OMT group significantly decreased compared to placebo (mean delta OMT - 326.00±491.24 mm2, p = 0.01). In the experimental group TLF showed a mean inclination reduction of 3.33 degrees after treatment (p = 0.044, mean d = 0.54). Moreover, a significant positive association between delta ECSA and delta TLF was observed (p = 0.04, r = 0.46). DISCUSSION: Among PD-PS patients, MIRT plus OMT showed preliminary evidence of postural control and TLF improvement, compared to the control group.

Effects of Constraint-Induced Movement Therapy on upper limb activity according to a bi-dimensional kinematic analysis in progressive multiple sclerosis patients: a randomized single-blind pilot study.

Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by demyelinization and axonal loss resulting, in 66% of cases, in upper limb motor impairment. The effects of constraint-induced movement therapy (CIMT) have recently been investigated in MS patients. The aim of this randomized single-blind pilot study was to assess the effects of CIMT on upper limb activity, specifically smoothness of movement, in patients affected by progressive MS. Patients affected by MS, and reporting reduced use primarily of one upper limb, were enrolled and randomly allocated to two different groups: a CIMT group, where treatment was performed with the less affected limb immobilized by a splint, and a control group, submitted to intensive bi-manual treatment. All evaluations were performed at baseline (T0) and after two weeks of treatment (T1) by an operator unaware of the patients' allocation. The primary outcome was the difference in movement smoothness, measured by means of a bidimensional kinematic evaluation. Secondary outcomes were: endpoint error and arm trajectory mean speed. Furthermore, patients performed the Hand Grip Strength Test (HGS) and 9-Hole Peg Test (9HPT), for both arms, at both time points. Ten patients with MS (4 males, 6 females; mean age 51.0±7.7 years) were randomly allocated to the CIMT group (n=5) and control group (n=5). There were no significant differences between groups in any of the data assessed at baseline. In the CIMT group subjects, the treatment effect, in terms of movement smoothness, was significant at the more affected limb (p=0.0376). The CIMT group displayed statistically significant improvements, versus the baseline values, in muscle strength (HGS:22.4±8.3 vs 26.0±6.0; p<0.05) and dexterity (9HPT: 31.8±6.1 vs 27.4±4.9; p<0.05) of the more affected limb. A positive, although not significant, trend in terms of muscle strength and upper limb dexterity was observed, for both limbs, in the control group after the two-week treatment. Bi-dimensional kinematic evaluation demonstrated that the CIMT group showed a significant reduction of endpoint error and higher mean speed for the more affected arm; these data are in line with the significant improvements recorded on the HGS and 9HPT. Moreover, in the CIMT group, a non-significant worsening of muscle strength was recorded for the less affected upper limb.

Effects of acoustic stimulus duration on cervical vestibular evoked myogenic potentials: A neurophysiological and modeling study.

OBJECTIVE: To analyze and model the effects of acoustic stimulus duration on cervical vestibular evoked myogenic potentials (cVEMPs). DESIGN: Subjects with normal hearing and no vestibular or cervical disorders were tested using 1 kHz tone bursts (TBs) of different durations to evoke cVEMPs from the ipsilateral sternocleidomastoid muscle. VEMP modeling was performed in Labview. RESULTS: The increase in TB duration initially resulted in a non-linear increase in cVEMP amplitude, followed by more complex cVEMP modifications that were mainly related to the appearance of a new wave (nX) that interfered with n23. With long TBs there were two distinct negative peaks with an identical threshold, suggesting a common vestibular nature. A two-level inhibition model qualitatively accounted for the two distinct negative peaks. However, good fitting of the cVEMP waveform required a multi-level model that included an excitatory phase after the inhibitory period. CONCLUSIONS: The two negative components (n23 and nX) observed in cVEMPs elicited by long TBs may result from the involvement of two different pathways with different dynamics or a single pathway with quick adaptation in the activity along the vestibulo-collic arc. Excitatory activity following the period of inhibition may represent rebound activity at the motor unit level.

Psoriasis and oral lesions: multicentric study of Oral Mucosa Diseases Italian Group (GIPMO).

OBJECTIVE: This is a multicentric, observational and controlled study designed to verify the existence of a significant association between plaque-type psoriasis and oral lesions, such as geographic tongue and/or fissured tongue. STUDY DESIGN: during a period of 9 months all consecutive patients with plaque-type psoriasis were enrolled using simple nonrandom (sequential) sampling. The control group included healthy subjects presenting to the same Dermatology centers to monitor pigmented skin lesions; the patients were matched for age and sex. All patients were examined for oral lesions. RESULTS: Out of a total of 535 psoriatic patients and 436 control group patients, oral mucosal lesions were detected in 188 (35.1%) and 86 (19.7%) cases, respectively, and the difference is statistically significant. Fissured tongue (FT) and geographic tongue (GT), which were most frequently detected, were seen more frequently in psoriatic patients (FT: 22.6%; GT: 9.1%) than the control group (FT: 10.3%; GT: 5.2%) (p<0.05). CONCLUSIONS: On the basis of the similar studies reported in the literature and the large number of patients involved in our study, we can conclude that FT and GT can be clearly suggested as oral manifestations of plaque-type psoriasis, although the reason for this association is not clear.

Non-linear recurrence analysis of NREM human sleep microstructure discloses deterministic oscillation patterns related to sleep stage transitions and sleep maintenance.

Sleep is a dynamic process aimed at obtaining the required neurophysiological states at certain times, according to circadian and homeostatic needs and despite external or internal interfering stimuli. In this context, peculiar transient synchronized EEG patterns (TSEP) are supposed to play the main role in the building up of EEG synchronization and in the flexible adaptation against perturbations Our study aimed at disclosing and quantifying attractor driven, hidden periodicity or, conversely, chaotic oscillation patterns in the series of these TSEP related to sleep stage transitions and sleep maintenance. At first we devised a multistep algorithm, able to capture TSEP from EEG during sleep in 10 healthy volunteers. The time series of TSEP were then analyzed according to the Recurrence Plot (RP). TSEP series showed to form a pseudo-periodic series which becomes progressively denser and more stable until steady slow wave NREM sleep is reached, but looses stability just before REM sleep starts. This suggests that deterministic oscillatory patterns maybe adequate descriptors of the balance between homeostatic needs for NREM sleep and REM sleep pressure, supported by different cortical neuronal populations interactions.

An atypical case of sporadic fatal insomnia.

Fatal insomnia is a rare human prion disease characterised by sleep-wake disturbances, thalamic degeneration and deposition of type 2 disease-specific prion protein (PrP(Sc)). This report details a patient with sporadic fatal insomnia who exhibited cerebral deposition of type 1 PrP(Sc) and neuropathological changes largely in the basal ganglia. Previous damage of this brain region by a surgically removed colloid cyst and the insertion of two intracerebral shunts may have influenced the distribution of PrP(Sc) through a chronic inflammatory process. These findings add to our knowledge of the phenotypic variability of human prion diseases with prominent sleep disturbances.

Automatic detection of transient EEG events during sleep can be improved using a multi-channel approach.

OBJECTIVE: Automatic methods developed to detect transient EEG events during sleep may present a degree of arbitrariness in the choice of appropriate channels or amplitude thresholds for the analysis. To overcome these limitations, we propose a multi-channel and temporal coincidences approach. METHODS: A two-step automatic detection (AD) of peculiar transient synchronized EEG events (TE) was performed in stage 2 and stage 3 sleep periods obtained from 10 normal sleep recordings and included: (a) detection of candidate TE from all the EEG traces and averaged signals, based on amplitude thresholds selections in both the time and frequency domains; (b) cross-checking of TE by evaluation of the coincidences in different EEG traces. TE found by AD but not confirmed by visual analysis (false positives, FP) and TE evidenced by visual analysis and missed by AD (false negatives, FN) were then counted. RESULTS: AD performed in averaged signals significantly reduced the number of FP but slightly increased FN, compared to single-channel analysis. However, when TE were confirmed by inter-channel temporal coincidences, a significant reduction of total errors (FN+FP) was achieved. The minimum error was obtained after C3-A2 and C4-A1 averaging and signal cross-checking with at least three channels (C3-A2 or C4-A1, plus both O1-A2 and O2-A1). CONCLUSIONS: This study describes a novel method for automatic detection of transient EEG events occurring during sleep that takes into account all the available channels. SIGNIFICANCE: This approach reduces the need of human supervision and may overcome most of the difficulties encountered by automatic methods based on single-channel analysis.

Recurrent cerebrovascular ischaemic events in patients with interatrial septal abnormalities: a follow-up study.

The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18-60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994-December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean+/-SD) of 64.1+/-28.8 months (range 8.1-105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p>0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.

Stroke in young patients: etiopathogenesis and risk factors in different age classes.

The aim of our study was to evaluate the etiopathogenesis and the vascular risk factors in a consecutive series of patients with juvenile ischemic stroke. We enrolled 273 patients (158 males and 115 females), aged between 16 and 49 years, with ischemic cerebrovascular events (ICVE), including transient ischemic attack (TIA) or stroke, referred to our neurology ward between January 1994 and December 2001. Our protocol included medical history, cardiac and neurological examinations, assessment of risk factors and laboratory tests. The instrumental assessment included transthoracic echocardiography (70%), transesophageal echocardiography (60%), conventional angiography (30%), MR angiography (30%), cranial computed tomography (100%) and brain MRI (48%). The ICVE was a stroke in 60% of the cases, a reversible ischemic neurologic deficit in 14% and a TIA in 26%. Thirty-three patients were aged less than 29, 59 were aged between 30 and 39 and 181 between 40 and 49. The percentage of females was higher in patients aged less than 29 while males were prevalent in the 4th and 5th decade. The patients were subtyped according to etiopathogenesis. A large-vessel disease (LVD) was diagnosed in 43 patients (16% of the cases), mostly in patients aged more than 40 years (36 cases). A small-vessel disease (SVD) was found in 48 patients (17% of cases), mostly in patients aged more than 40 years (41 cases). A cardioembolic stroke (CE) was diagnosed in 66 patients (24% of the cases). In the majority of the cases, the cardiopathies were at low-uncertain embolic risk: patent foramen ovale (PFO, 39 cases, in 8 patients associated with an atrial septal aneurism), atrial septal aneurism (12 cases) and myxomatous mitral valve prolapse (3 cases). Stroke due to other causes was found in 51 patients (19% of the cases). Arterial dissection, more frequently involving the carotid region, was diagnosed in 35 patients. Coagulopathies and vasculitis were found in 5 and 6 patients, respectively. Stroke of unknown etiology was found in 65 patients (24% of the cases) with a homogeneous distribution among decades. Our study highlights the role of minor cardiac sources of embolism and arterial dissection in the etiology of juvenile ischemic stroke, whereas coagulopathies and vasculitis are less relevant. LVD and SVD were relevant only in the 5th decade.

Nocturnal anomalous movement reduction and sleep microstructure analysis in parkinsonian patients during 1-night transdermal apomorphine treatment.

This study analyzed the macrostructure and microstructure of sleep in 12 parkinsonian patients under basal conditions (T0) and during 1-night treatment (T1) with a new formulation of apomorphine. This new formulation consisted in a microemulsion of apomorphine administered by the transdermal route, able to provide a constant release of the drug over several hours (APO-TD). Sleep analysis at T1 compared with T0 revealed a 16% increment of total sleep time, a 12% increment of sleep efficiency, a 16% increment of stage 3 and 4 non-REM sleep, a 15% reduction of periodic limb movements index, a 22% reduction of arousal index, and a 23% reduction of cycling alternating patterns/non-REM. We conclude that APO-TD may be able to reduce nocturnal anomalous movements, akinesia, and rigidity in Parkinson's disease, and may reduce the disturbed sleep typical of Parkinson's disease.

Quantitative electroencephalographic findings in beagles anaesthetized with propofol.

The purpose of this study was to assess quantitative electroencephalography (q-EEG) in 10 healthy beagle dogs under propofol anaesthesia in order to determine objective guidelines for diagnostic electroencephalographic (EEG) recordings and interpretation. The basic pattern after preliminary visual examination of EEG recordings was characterized by spindles, k-complexes, vertex sharp transients, and positive occipital transients that were superimposed on the slow background activity. The results of the q-EEG were characterized by the prevalence of slow rhythms delta and theta, both in absolute and relative power spectrum analysis, while fast rhythms (alpha and beta) were poorly represented. The distribution of single frequency bands was widespread for delta, focal for frontal and central for theta, as well as for most alpha and beta patterns. The present study has shown that the use of quantitative EEG gives information on the frequency content of the bio-electrical activity and defines the distribution of the single frequency bands under a standardized anaesthetic protocol.

Are the neurophysiological techniques useful for the diagnosis of diaphragmatic impairment in multiple sclerosis (MS)?

OBJECTIVE: To characterize cortico-diaphragmatic pathway involvement in multiple sclerosis (MS) by means of transcranial magnetic stimulation (TMS), and verify its clinical impact. METHODS: TMS from diaphragm (Dia), and abductor digiti minimi (AbdV degrees ) was performed in 26 MS patients. Phrenic nerve (PN) conduction study was also performed. Expanded disability status scale (EDSS) and fatigue descriptive scale (FDS) were measured. Forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), peak expiratory flow (PEF) were tested: the predicted percentage value (% pred) was considered. RESULTS: Cortical motor evoked potential (Cx-MEP) latency and central motor conduction time (CMCT) were prolonged, respectively, in 31 and 23% of patients from Dia, in 76 and 79% from AbdV degrees. PN-compound motor action potential (CMAP) was normal. EDSS correlated to Cx-MEP from AbdV degrees (P<0.01), and PN-CMAP amplitude (P<0.05), FEV1 % pred (P<0.01), PEF % pred (P<0.01). PN-CMAP amplitude correlated to FVC % pred P=0.05, FEV1 % pred P<0.01, PEF % pred P<0.01. Fatigue was related to AbdV degrees Cx-MEP and CMCT (P<0.05 and P<0.01). CONCLUSIONS: Cortico-diaphragmatic pathway is impaired only in a minority of MS patients. Lack of correlation between TMS findings from Dia and respiratory tests argues against its routinary use to detect subclinical respiratory alterations. Fatigue seems to be related to the motor impairment rather than to respiratory distress.

Noun verb dissociation in Parkinson's disease.

A noun/verb dissociation with a relative verb deficit was found in patients affected by Parkinson's disease, even in relatively early stages, when mental deterioration is not severe. This finding is compatible with earlier observations, according to which verbs are dealt with in more anterior regions with respect to nouns. It also supports the speculation that the co-ordination and the manipulation of information associated with a verb world rely on the frontostriatal system.

Transoesophageal echocardiography in patients without arterial and major cardiac sources of embolism: difference between stroke subtypes.

We studied the records of 175 consecutive patients referred to our neurologic ward between January 1994 and February 2000 with a diagnosis of ischaemic cerebrovascular disease (ICVD) (stroke or transient ischaemic attack - TIA) who underwent transoesophageal echocardiography (TEE). We excluded patients with large vessel disease, high-risk embolic cardiopathies and other rare causes of stroke. According to clinical and neuroimaging findings, patients were divided into two groups. The lacunar (LAC) group (69/175 (39.4%)) and the nonlacunar (N-LAC) one (106/175 (60.6%)). The control population consisted of 78 consecutive patients, referred to the echocardiography laboratory for TEE without history of ICVD and known heart disorders. Patent foramen ovale (PFO) frequency was significantly higher in case patients than in control subjects (55/175 (31.4%) vs. 13/78 (16.6%); p = 0.02). Among case patients, PFO was more prevalent in the N-LAC group than in the LAC one (43/106 (40.6%) vs. 12/69 (17.4%); p = 0.0005). A large degree of shunt occurred in 53.5% of N-LAC patients and in 16.7% of LAC ones (p = 0.04). Atrial septal aneurysm (ASA) was detected in 12% of case patients and 1.3% of control subjects (p = 0.003) and was more frequent in the N-LAC group than in the LAC one (16 vs. 5.8%; p = 0.05). Mitral prolapse (MP) was present in 6/175 (3.4%) ICVD patients (vs. 1/78 among controls) in most cases associated with myxomatous valve redundancy. Aortic arch atheromas (AA) were detected in 12% of ICVD patients and in 10.2% of controls. The frequency was 9.4% in N-LAC and 15.9 in LAC. No complicated AA (plaque thickness >4 mm, ulcerated atheroma, superimposed thrombus) were detected. After multivariate analysis, PFO (OR = 3.8; 95% CI = 2.7-7.9) and ASA (OR = 8.01; 95% CI = 3.0-16.1) appeared to be independent predictors of ICVD. PFO (OR = 2.24; 95% CI = 1.24-4.92) was also independently associated with N-LAC stroke subtype and its importance was even higher in younger patients. Our study provides further evidence that TEE is a helpful diagnostic tool in stroke patients without arterial and major cardiac sources of embolism. However, its utility differs according to type and localization of the ischaemic lesion being more relevant in patient with N-LAC infarctions.

Controlled-release transdermal apomorphine treatment for motor fluctuations in Parkinson's disease.

This study evaluated the efficacy in Parkinson's disease (PD) of a new pharmacologic preparation of apomorphine included in microemulsions and administered by transdermal route, which provides a constant release of the drug for several hours (Apo-TD). Twenty-one PD patients with motor fluctuations were treated with L-dopa alone, with L-dopa plus oral dopamine-agonists, or with L-dopa plus Apo-TD. Apo-TD improved UPDRS-III and tapping test scores in "off" conditions, and reduced duration of "off" periods; no improvement in "on" conditions occurred. We conclude that Apo-TD shows its efficacy particularly by reducing "off" period duration and disability rather than improving motor performances in "on" conditions and therefore it seems a promising treatment for uncontrolled "off" phases in PD patients.

Common daily activities in the virtual environment: a preliminary study in parkinsonian patients.

Patients with Parkinson's disease (PD) create behavioral motor strategies by using external cues to facilitate their movements. Virtual reality (VR) could work as an external stimulus in order to explore the motor plans by means of creation of mental images. We tested 2 women with PD aged 68 and 69 years, and 10 normal control subjects. Patients underwent a neuropsychological assessment to evaluate cognitive abilities involved in the tasks required by the VR session. VR environment reproduces common daily activities situations at home, such as eating or using the bathroom. VR describes the alterations of the motor plans in PD by a point of view different from the clinical one, by testing "pure" mental sequences of the execution of a movement, without the interference of motor disability.

Bullous pemphigoid in Liguria: a 2-year survey.

BACKGROUND: The epidemiology of bullous pemphigoid (BP) is not clear because of the heterogeneity of the disease, and its possible association with internal malignancies has been under debate for many years. We report the findings of a 2-year study on incident BP cases in the Liguria region of Italy. SUBJECTS AND METHODS: Thirty-two patients with BP were collected over the 2-year period. Diagnosis was made based on clinical findings and confirmed by histology, direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) with salt-split skin and monkey oesophagus, and immunoblotting (IB). All patients were thoroughly investigated for possible malignancies and all were followed up for 6 months to monitor the response to treatment. RESULTS: DIF showed linear deposits at the dermoepidermal junction in all but one patient. IIF gave positive findings for 15 sera tested with monkey oesophagus and 20 tested with salt-split skin. IB gave positive findings in 19 cases. There was a malignancy in six cases, but no clinical or immunological features that could be considered to predict this occurrence. CONCLUSIONS: The findings of this study are in accordance with most of the data found in the literature, including the fact that IgG serum levels did not predict the course of the disease. Contrary to previous indications, IgE levels were not indicative of disease course either. Mucosal lesions, erythema multiform-like lesions, negative IIF findings and antibodies to AgPB2 were not a prediction for the development of malignancy.