Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

Neurological soft signs in primary headache patients.

Neurological soft signs (NSS) are semeiotic anomalies not assessed by the standard neurological examination, primarily developed in psychiatric settings and recently proposed as potential markers of minor brain circuit alterations, especially the cerebellar-thalamic-prefrontal network. Primary headache patients present with normal neurological examination and frequent psychiatric comorbidity. Aim of this exploratory study consisted in assessing NSS in 20 episodic frequent migraine (MH) and in 10 tension-type headache (ETTH) outpatients compared to 30 matched healthy controls. NSS were assessed by the Heidelberg scale; clinical characteristics and brain MRI were additionally obtained in all patients. NSS were increased by ∼70 and ∼90% in ETTH and MH, respectively, with respect to controls (p<0.001) and the difference remained significant even after controlling for age and education. Headache type and characteristics did not influence NSS presentation, while headache patients with white matter hyperintensities (WMH) at brain MRI had higher NSS scores compared both to normal controls and patients without WMH. NSS identify a subset of primary headache patients sharing the same comorbidities or minimal brain anomalies, suggesting that tailored prophylactic options might apply.

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.

Decreased whole-blood global DNA methylation is related to serum hormones in anorexia nervosa adolescents.

OBJECTIVES: The one-carbon metabolism, also known as methionine-homocysteine cycle, governs the dynamics of DNA methylation, epigenetically regulating gene expression, and has been reported altered in anorexia nervosa (AN) adult patients. The aim of this study consisted in assessing whole-blood DNA methylation in adolescent AN patients, assessing its significance in relationship to clinical and hormonal variables. METHODS: Whole-blood global DNA methylation was measured as incorporation of [(3)H]dCTP following HpaII cut in 32 adolescent females affected by restrictive type AN and compared to 13 healthy controls. Homocysteine, vitamin B12 and folate plasma levels were assessed as well as fasting plasma levels of leptin and steroid hormones. Clinical variables, including severity and associate states and traits, were assessed by means of the EDI-3, CDI and STAI-Y scales. RESULTS: We confirm that whole-blood global DNA methylation is modestly albeit significantly reduced in AN adolescents with respect to controls, correlating with plasma leptin and steroid hormone levels. Conversely, clinical traits did not correlate with the outcome variable. CONCLUSIONS: A better definition of the epigenetic dysregulation underlying AN pathology or vulnerability might lead to develop useful markers for diagnosis, prognostic classification and tailored therapeutic interventions in these vulnerable patients since the earliest phases of their disease.

Assessing glutamatergic function and dysfunction in peripheral tissues.

Glutamate is the major mediator of excitatory signaling in the mammalian central nervous system (CNS) and it has recently been described to have a central role in the transduction of sensory input in the peripheral nervous system (PNS), too. However, functional glutamatergic systems are expressed by peripheral non-neural tissues as well, such as heart, kidney, lungs, ovary, testis, blood and skin. Interestingly, glutamatergic alterations have been repeatedly described in these tissues in various neuropsychiatric diseases. Here we will review evidence suggesting that glutamate measurements obtained from sampling ex vivo peripheral cells can permit the assessment of the dynamics of glutamate release, uptake, receptor-mediated signaling, synthesis and degradation, and mirror homologous dysfunctions operative within the CNS in each single patient. Among all the available cell types we will focus on leukocytes, platelets and fibroblasts that can be easily obtained from patients multiple times without concerns related to post-mortem changes. Finally, we will briefly review another possibility, offered by testing plasma (and CSF) glutamate levels, allowing the indirect investigation of glutamate-mediated crosstalk between central and peripheral compartments. Technical pitfalls of these biomarkers will be contextually emphasized.

The hand pronation phenomenon: a franco-german tale.

The hand pronation phenomenon due to a pyramidal tract lesion is a sign commonly used for identifying a mild paresis, but the first descriptions of this maneuver seem to have been only partially investigated by the historians of neuroscience. Here we illustrate that this sign was most probably originally described by Adolf Strümpell (1853-1925) in 1901 and subsequently re-proposed by the illustrious French neurologist Joseph Babinski (1857-1932) in 1907, although with a slightly different focus of application. Finally, the Pronationsphaenomen was analyzed in detail in the subsequent work of Nikolaus Gierlich (1865-1944), a less-known German neurologist who tried one of the first detailed reports of the phylogenetic significance of this sign, publishing a paper in 1925. These works are reported here, detailing the existing discrepancies, along with notes on the relevant surrounding historical context. In particular, the undervalued contribution of Gierlich to the history of neuroscience and to the phylogenetic approach to semeiotics is analyzed in more detail and acknowledged.

Early-onset SCA17 with 43 TBP repeats: expanding the phenotype?

The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient's entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17.

The disease of the moon: the linguistic and pathological evolution of the English term "lunatic".

The public opinion and the scientific community incorrectly believe that the English term "lunatic" was originally related only to insanity, but it also referred to epileptic people. The aim of this article is to clarify the original meaning of the English word "lunatic" by analyzing the evolution of the relationship between psychiatric and neurological diseases and by pointing out the influence of the moon in the history of medicine, in popular traditions, and in English literature. The article also contains a detailed and accurate review of the modern scientific literature on the relationship between moon and epilepsy/psychiatric disorders.

Epigenetic GABAergic targets in schizophrenia and bipolar disorder.

It is becoming increasingly clear that a dysfunction of the GABAergic/glutamatergic network in telencephalic brain structures may be the pathogenetic mechanism underlying psychotic symptoms in schizophrenia (SZ) and bipolar (BP) disorder patients. Data obtained in Costa's laboratory (1996-2009) suggest that this dysfunction may be mediated primarily by a downregulation in the expression of GABAergic genes (e.g., glutamic acid decarboxylase67[GAD67] and reelin) associated with DNA methyltransferase (DNMT)-dependent hypermethylation of their promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that induce DNA-demethylation when administered at doses that facilitate chromatin remodeling. The benefits elicited by combining VPA with antipsychotics in the treatment of BP disorder suggest that an investigation of the epigenetic interaction of these drugs is warranted. Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA's action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors. By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising treatment strategy for normalizing GABAergic promoter hypermethylation and the GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP disorder patients. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Narrowing the window for 'senile chorea': a case with primary antiphospholipid syndrome.

Several apparently idiopathic cases of so called 'senile chorea' have been recently redefined by the availability of brain MRI scan and the clinical introduction of genetic testing for Huntington's disease. Cases currently still regarded as idiopathic might yet be attributed to other medical conditions. Chorea as a unique manifestation of a primary antiphospholipid syndrome (PAPS) has so far been described only in young and middle-aged subjects. Here, we report a typical case of 'senile chorea' associated with PAPS, thus expanding the potential underlying etiologies and further narrowing the window of primary 'senile chorea'.

Targeting cancer and neuropathy with histone deacetylase inhibitors: two birds with one stone?

Histone deacetylase inhibitors (HDACi) belong to a novel class of drugs able to act on the epigenome, indirectly remodeling the spatial conformation of the chromatin: by increasing histone acetylation these drugs ultimately promote the detachment of the DNA from the nucleosome octamer, therefore allowing the access of transcription factors to the double helix. Such a mechanism of action is of particular interest in the field of cancer treatment, considering the reactivation of silenced tumor suppressor genes as an important target at which aiming; indeed, it is currently believed that dysregulation of the epigenome plays a major role in cancer. Interestingly, some of the compounds belonging to the HDACi family have also additional therapeutic properties, as in the case of valproate that may ameliorate neuropathic pain in animal models and in patients. Conceivably, this is a remarkable observation, since peripheral neuropathy is a potentially severe side effect of several classes of anticancer agents, such as platinum-derived drugs, antitubulins or protesome inhibitors, limiting an effective treatment of the underlying cancer. Based on these data, in this review we will argue that, with respect to other nowadays available anticancer agents, HDACi might offer the advantage not only to target the neoplastic disorder, but also to prevent peripheral neuropathies, possibly displaying a complementary mechanism of action.

Third cranial nerve palsy? Look for a sicca syndrome.

Sjogren's syndrome (SS) is a systemic autoimmune disorder, and neurological involvement may frequently occur. Here we describe a 79-year-old woman who came to our attention for a sudden right incomplete 3rd cranial nerve palsy. Following extensive investigations, a diagnosis of primary SS was reached, and the patient recovered after treatment with ev Ig and steroids. Therefore, we suggest that SS should be considered in apparently idiopathic 3rd cranial nerve palsies, since, with the appropriate treatment, they might be transient and reversible.