Duration, numerosity and length processing in healthy ageing and Parkinson's disease.

People constantly process temporal, numerical, and length information in everyday activities and interactions with the environment. However, it is unclear whether quantity perception changes during ageing. Previous studies have provided heterogeneous results, sometimes showing an age-related effect on a particular quantity, and other times reporting no differences between young and elderly samples. However, three dimensions were never compared within the same study. Here, we conducted two experiments with the aim of investigating the processing of duration, numerosity and length in both healthy and pathological ageing. The experimental paradigm consisted of three bisection tasks in which participants were asked to judge whether the presented stimulus (i.e. a time interval, a group of dots, or a line) was more similar to the short/few or long/many standards. The first study recruited healthy young and elderly participants, while the second recruited healthy elderly participants and patients with Parkinson's disease, a clinical condition commonly associated with temporal impairments. The results of both experiments showed that discrimination precision differed between domains in all groups, with higher precision in the numerosity task and lower sensitivity in judging duration. Furthermore, while discrimination abilities were affected in healthy elderly and, even more so, in Parkinson's disease group, no domain-specific impairments emerged. According to our research, reduced discrimination precision might be explained by an alteration of a single system for all quantities or by an age-related general cognitive decline.

Impaired circadian heart rate variability in Parkinson's disease: a time-domain analysis in ambulatory setting.

BACKGROUND: Heart rate variability (HRV) decreases in Parkinson's disease (PD) and it can be considered a marker for cardiovascular dysautonomia. The purpose of this pilot study is to evaluate long-term time-domain analysis of HRV of PD patients and compare the results with those of matched healthy individuals. METHODS: Idiopathic PD patients without comorbidity impairing HRV, and age-matched healthy individuals were recruited in a pilot study. A long-term time domain analysis of HRV using 24-h ambulatory ECG was performed. RESULTS: Overall, 18 PD patients fulfilling inclusion criteria completed the evaluation (mean age was 55.6 ± 8.8, disease duration: 5.0 ± 4.7). Mean SCOPA-AUT score was 10.1 ± 7.3. Patients were on Hoehn & Yahr stage 1-2 and mean Levodopa Equivalent Dose (LED) was 311 ± 239.9. Mean of the 5-min standard deviation (SD) of R-R intervals distribution (SDNN) for all 5 min segments of the entire recording (ISDNN) was significantly lower in patients compared to controls. ISDNN was significantly different between Parkinson's disease patients and healthy controls. CONCLUSIONS: In our population characterized by mild to moderate disease severity, time-domain assessment of HRV seemed to be a potential tool to characterize cardiovascular dysautonomia. Decrease of ISDNN in PD may reflect an autonomic derangement extending all day and night long.

Red Ear Syndrome.

The Red Ear syndrome (RES) is an intriguing syndrome originally described for the first time nearly 20 years ago. RES is characterized by unilateral/bilateral episodes of pain and burning sensation of the ear, associated with ipsilateral erythema. RES episodes are indeed isolated in some patients, but they can occur in association with primary headaches, including in particular migraine in the developmental age. Although the underlying pathophysiological mechanisms are still uncertain, in the recent years the described comorbidities have aroused increasing interest because of possible clinical implications. Moreover, RES seems to be more often associated with clinical features of migraine partially provoked by the involvement of the parasympathetic system. This clinical association has shed new light on the pathophysiology of RES, supporting the hypothesis of a shared pathophysiological background, for example, through the activation of the trigeminal autonomic reflex. Current therapies of RES will be also discussed. Finally, we will resume the more controversial aspects of this relatively new and probably underestimated neurological syndrome.

Neuregulin 1 signalling modulates mGluR1 function in mesencephalic dopaminergic neurons.

Neuregulin 1 (NRG1) is a trophic factor that has an essential role in the nervous system by modulating neurodevelopment, neurotransmission and synaptic plasticity. Despite the evidence that NRG1 and its receptors, ErbB tyrosine kinases, are expressed in mesencephalic dopaminergic nuclei and their functional alterations are reported in schizophrenia and Parkinson's disease, the role of NRG1/ErbB signalling in dopaminergic neurons remains unclear. Here we found that NRG1 selectively increases the metabotropic glutamate receptor 1 (mGluR1)-activated currents by inducing synthesis and trafficking to membrane of functional receptors and stimulates phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which is required for mGluR1 function. Notably, an endogenous NRG1/ErbB tone is necessary to maintain mGluR1 function, by preserving its surface membrane expression in dopaminergic neurons. Consequently, it enables striatal mGluR1-induced dopamine outflow in in vivo conditions. Our results identify a novel role of NRG1 in the dopaminergic neurons, whose functional alteration might contribute to devastating diseases, such as schizophrenia and Parkinson's disease.

Migraine and cranial autonomic symptoms in children and adolescents: a clinical study.

The frequency of cranial autonomic symptoms in children affected by primary headaches is uncertain. The aim of our study was to estimate the frequency of symptoms in pediatric headaches and correlate it with main migraine characteristics. A questionnaire investigating the presence of cranial autonomic symptoms was administered to all children with primary headache for 2 years. A total of 230 children with primary headache (105 males, 125 females) were included. Two hundred two children were affected by migraine and 28 (12.2%) by other primary headaches. Cranial autonomic symptoms were significantly complained by migraineurs (55% vs. 17.8%) (P < .001) and by children with higher frequency of migraine attacks (odds ratio = 2.6, confidence interval = 1.4-4.7, P = .001). Our findings show that cranial autonomic symptoms are rather common during pediatric migraine attacks. The association between cranial autonomic symptoms and higher frequency of attacks might suggest the role of the trigeminal-autonomic reflex in migraine pathophysiology.

Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons.

Mitochondria are key organelles for the maintenance of life and death of the cell, and their morphology is controlled by continual and balanced fission and fusion dynamics. A balance between these events is mandatory for normal mitochondrial and neuronal function, and emerging evidence indicates that mitochondria undergo extensive fission at an early stage during programmed cell death in several neurodegenerative diseases. A pathway for selective degradation of damaged mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to sustain neuronal viability. In the present work, we analyzed the effect of autophagy stimulation on mitochondrial function and dynamics in a model of remote degeneration after focal cerebellar lesion. We provided evidence that lesion of a cerebellar hemisphere causes mitochondria depolarization in axotomized precerebellar neurons associated with PTEN-induced putative kinase 1 accumulation and Parkin translocation to mitochondria, block of mitochondrial fusion by Mfn1 degradation, increase of calcineurin activity and dynamin-related protein 1 translocation to mitochondria, and consequent mitochondrial fission. Here we suggest that the observed neuroprotective effect of rapamycin is the result of a dual role: (1) stimulation of autophagy leading to damaged mitochondria removal and (2) enhancement of mitochondria fission to allow their elimination by mitophagy. The involvement of mitochondrial dynamics and mitophagy in brain injury, especially in the context of remote degeneration after acute focal brain damage, has not yet been investigated, and these findings may offer new target for therapeutic intervention to improve functional outcomes following acute brain damage.

Emerging role of mitochondria dysfunction in the onset of neurodegenerative diseases.

Mitochondria play a pivotal role in a number of biochemical processes in the neuron including energy metabolism and ATP production, intracellular Ca2+ homeostasis and cell signalling which are all implicated in the regulation of neuronal excitability. For this reason, it is not surprising that alterations in mitochondrial function have emerged as a hallmark of aging and various age-related neurodegenerative diseases in which a progressive functional decline of mitochondria has been described. The evidence that mitochondria are concentrated in synapses, together with the observation that synaptic dysfunction identifies an early forerunner of a later neurodegeneration, strongly suggests that significant alterations to synaptic mitochondrial localization, number, morphology, or function can be detrimental to synaptic transmission and might characterize the early stages of many neurological diseases. Thus, the characterization of both molecular players and pathway involved in mitochondria dysfunction will provide new chances to identify pharmacological target for new mitochondria-based drugs aimed at interrupting or slowing down pathological processes and/or ameliorating symptoms of neurological disorders. In this review we provide a current view on the role of mitochondria for neuronal function and how mitochondrial functions impinge on neurological diseases.

Prevalence of red ear syndrome in juvenile primary headaches.

BACKGROUND: Previous studies have suggested a relationship between 'red ear syndrome' (RES) and pediatric migraine. Aims of this study were (i) to assess the frequency, specificity and sensitivity of RES in a population of pediatric migraineurs and (ii) to establish the pathophysiological mechanisms of RES associated with migraine. METHODS AND RESULTS: A total of 226 children suffering from headache (aged 4-17 years) were enrolled. One hundred and seventy-two (76.4%) were affected by migraine, the remaining 54 (23.6%) by other primary headaches. RES was followed significantly more frequently by migraine (23.3%; p < .0001), and was characterized by high specificity and positive predictive value (96.3 and 95.3%, respectively). According to the univariate statistical analysis, RES showed a statistically significant association with male gender, throbbing quality of the pain, vomiting and phonophobia. It was confirmed by a multivariate stepwise logistic regression model only for the throbbing quality of the pain, vomiting and male gender. CONCLUSIONS: Our study showed that (i) in children, RES is a highly specific sign for migraine. In addition, the evidence of an association of RES with some migraine features partially provoked by the parasympathetic system supports the hypothesis of a shared pathophysiological background (e.g. via the activation of the trigeminal-autonomic reflex).

Multiple sclerosis survival: a population-based study in Sicily.

BACKGROUND AND PURPOSE: There are few population-based surveys on multiple sclerosis (MS) survival. To investigate MS survival in MS patients recruited during surveys conducted in Sicily. METHODS: Multiple sclerosis patients identified during previous surveys were randomly matched to two referent subjects by residence, year of birth, and gender. Living status was obtained by municipality records (end of follow-up June, 30th 2007) and, for the deceased, date and causes of death were searched. Kaplan-Meier plots were used to calculate differences in mortality between MS patients and referent subjects. MS risks for mortality with 95% confidence intervals (CI) were also calculated. RESULTS: We included 194 MS patients and 388 matched persons. Thirty MS patients (15.5%) and 28 referents (7.2%) had died until the end of follow-up. Mean survival from onset of the disease to death was 20.6 years. Mean age at death was 55.5 for MS patients and 64.8 for the referents. Adjusted Hazard Ratios for mortality in MS was 1.81 (95% CI 1.36-2.40). Kaplan-Meier estimates showed a higher mortality amongst patients compared to referent subjects (P < 0.001). CONCLUSIONS: The present study confirms the higher mortality risk in MS patients with no significant gender difference. Causes of death are related to complications of high disability and to increasing age.

Neuronal caspase-3 signaling: not only cell death.

Caspases are a family of cysteinyl aspartate-specific proteases that are highly conserved in multicellular organisms and function as central regulators of apoptosis. A member of this family, caspase-3, has been identified as a key mediator of apoptosis in neuronal cells. Recent studies in snail, fly and rat suggest that caspase-3 also functions as a regulatory molecule in neurogenesis and synaptic activity. In this study, in addition to providing an overview of the mechanism of caspase-3 activation, we review genetic and pharmacological studies of apoptotic and nonapoptotic functions of caspase-3 and discuss the regulatory mechanism of caspase-3 for executing nonapoptotic functions in the central nervous system. Knowledge of biochemical pathway(s) for nonapoptotic activation and modulation of caspase-3 has potential implications for the understanding of synaptic failure in the pathophysiology of neurological disorders. Fine-tuning of caspase-3 lays down a new challenge in identifying pharmacological avenues for treatment of many neurological disorders.

Blood levels of homocysteine, cysteine, glutathione, folic acid, and vitamin B12 in the acute phase of atherothrombotic stroke.

Blood levels of total homocysteine (tHcy), cysteine (Cys), total and reduced glutathione (tGSH and rGSH), folic acid (FA), and vitamin B12 (B12) change during ischemic stroke as accompaniment of the tissue damage. The relationship between these changes remains scantly investigated. We evaluated the variation of these molecules in the 48 h after acute large artery atherothrombotic stroke (LAAS) and searched for the presence of matched variation of them. The study involved 50 subjects affected by acute LAAS and 49 healthy controls. Plasma levels of tHcy and Cys were significantly higher and serum levels of FA and B12 and plasma levels of rGSH were significantly lower in the patients than in the control group. Acute LAAS was associated with increased Hcy-decreased tGSH and decreased FA/tGSH. Pathways involved in cellular stress and in tissue repair are activated during acute LAAS.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study.

BACKGROUND: To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. METHODS: Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. RESULTS: The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. CONCLUSIONS: In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Body mass index does not change before Parkinson's disease onset.

BACKGROUND AND PURPOSE: Previous studies on the association between Parkinson's disease (PD) and body mass index (BMI) have reported conflicting results. We investigated the relationship between PD and BMI by a case-control study. METHODS: PD patients were randomly matched to healthy individuals by sex and age. BMI distribution in cases has been compared with BMI of controls and odd ratios (ORs) with 95% CI were calculated. RESULTS: We included 318 PD patients and 318 controls. We observed no association between PD and BMI. BMI distribution in cases and controls was similar also when we adjusted for diabetes, hypercholesterolemia and the time elapsed between PD onset and the interview (OR = 0.99; CI = 0.94-1.03; P = 0.51). CONCLUSIONS: These results did not confirm the previously reported association between PD and BMI. Population characteristics and methodological issues may partially account for the differences observed between the present study and the others.

Faf1 is expressed during neurodevelopment and is involved in Apaf1-dependent caspase-3 activation in proneural cells.

Fas-associated factor 1 (Faf1) has been described as a Fas-binding pro-apoptotic protein and as a component of the death-inducing signaling complex (DISC) in Fas-mediated apoptosis. Faf1 is able to potentiate Fas-induced apoptosis in several cell lines, although its specific functions are still not clear. Here we show that Faf1 is highly expressed in several areas of the developing telencephalon. Its expression pattern appears to be dynamic at different embryonic stages and to be progressively confined within limited territories. To decipher the specific role of Faf1 in developing brain, we used cDNA over-expression and mRNA down-regulation experiments to modulate Faf1 expression in telencephalic neural precursor cells, and we showed that in neural cell death Faf1 acts as a Fas-independent apoptotic enhancer. Moreover, we found that Faf1 protein level is down-regulated during apoptosis in a caspase- and Apaf1-dependent manner.

Prevalence of Parkinson's disease and other types of parkinsonism in the Aeolian Archipelago, Sicily.

OBJECTIVE: To estimate prevalence of Parkinson's disease (PD) and other types of parkinsonism in the Aeolian Archipelago, Sicily. METHODS: We studied the frequency of PD and other types of parkinsonism in the Aeolian Archipelago (population 13,431). All potential cases were identified from available medical information sources. To ensure the completeness of the case-findings, a screening questionnaire was also mailed to residents aged 40 years and over. Subjects were considered prevalent if they fulfilled the SNES diagnostic criteria for PD, on prevalence day (January 1, 2001). RESULTS: We identified 17 patients with parkinsonism from medical sources, and 4 from mail-survey. Prevalence for all types of parkinsonism was 156.3/100,000 (95% CI 99.4-234.8). Fourteen subjects fulfilled diagnostic criteria for PD giving a crude prevalence of 104.2/100,000 (95% CI 59.4-170.7) and 422.5/100,000 in the population aged 60 years and over. CONCLUSIONS: Prevalence of all types of parkinsonism and PD found in the Aeolian Archipelago is lower than that previously reported in Sicily.

Mortality in multiple sclerosis: a review.

This work was undertaken to evaluate studies on mortality caused by multiple sclerosis (MS), to evaluate if useful inferences can be drawn from survival studies that can be applied to clinical practice. A literature search was carried out to find epidemiological studies on MS prognosis, survival, mortality and causes of death relevant to our aim. The World Health Organization (WHO) reports on worldwide cause-specific mortality were also considered. Studies were evaluated according to the duration of the follow-up study, the year of publication and the methodology used. We evaluated MS survival from a methodological point of view and considered if time trends could be drawn from study results. We conclude that mortality is only slightly higher in MS patients when compared with that in the general population. Mortality is higher particularly for older patients and those with longer disease duration.

Dropped head as an unusual presenting sign of myasthenia gravis.

Prominent or isolated weakness of cervical extensor muscles is a relatively rare clinical sign. Commonly, this is known as "dropped-head syndrome". This abnormal flexion of the head may occur in a variety of neuromuscular diseases and in a few non-neurological disorders as well. The case we describe concerns a 61-year-old woman with dropped-head syndrome as the unique complaint of myasthenia gravis.

Long-term survival of Parkinson's disease: a population-based study.

In a set of a population- based study, long-term survival of 59 prevalent PD patients was compared with that of individuals free of neurological diseases matched 1:2 by sex and age of enrolment. PD individuals, compared with reference subjects, showed a two-fold increased risk of death (OR 2.1; 95 % CI 1.4, 3.1). Among causes of death, pneumonia and cachexia were significantly more frequent among PD patients than among individuals free of neurological diseases. We confirmed in a long-term follow-up study an increased mortality among PD individuals compared with that of the general population.