Lithium engages autophagy for neuroprotection and neuroplasticity: Translational evidence for therapy.

Here an overview is provided on therapeutic/neuroprotective effects of Lithifum (Li+) in neurodegenerative and psychiatric disorders focusing on the conspicuous action of Li+ through autophagy. The effects on the autophagy machinery remain the key molecular mechanisms to explain the protective effects of Li+ for neurodegenerative diseases, offering potential therapeutic strategies for the treatment of neuropsychiatric disorders and emphasizes a crossroad linking autophagy, neurodegenerative disorders, and mood stabilization. Sensitization by psychostimulants points to several mechanisms involved in psychopathology, most also crucial in neurodegenerative disorders. Evidence shows the involvement of autophagy and metabotropic Glutamate receptors-5 (mGluR5) in neurodegeneration due to methamphetamine neurotoxicity as well as in neuroprotection, both in vitro and in vivo models. More recently, Li+ was shown to modulate autophagy through its action on mGluR5, thus pointing to an additional way of autophagy engagement by Li+ and to a substantial role of mGluR5 in neuroprotection related to neural e neuropsychiatry diseases. We propose Li+ engagement of autophagy through the canonical mechanisms of autophagy machinery and through the intermediary of mGluR5.

Brain metabolic correlates of Locus Coeruleus degeneration in Alzheimer's disease: a multimodal neuroimaging study.

Locus Coeruleus (LC) degeneration occurs early in Alzheimer's disease (AD) and this could affect several brain regions innervated by LC noradrenergic axon terminals, as these bear neuroprotective effects and modulate neurovascular coupling/neuronal activity. We used LC-sensitive Magnetic Resonance imaging (MRI) sequences enabling LC integrity quantification, and [18F]Fluorodeoxyglucose (FDG) PET, to investigate the association of LC-MRI changes with brain glucose metabolism in cognitively impaired patients (30 amnesticMCI and 13 demented ones). Fifteen cognitively intact age-matched controls (HCs) were submitted only to LC-MRI for comparison with patients. Voxel-wise regression analyses of [18F]FDG images were conducted using the LC-MRI parameters signal intensity (LCCR) and LC-belonging voxels (LCVOX). Both LCCR and LCVOX were significantly lower in patients compared to HCs, and were directly associated with [18F]FDG uptake in fronto-parietal cortical areas, mainly involving the left hemisphere (p < 0.001, kE > 100). These results suggest a possible association between LC degeneration and cortical hypometabolism in degenerative cognitive impairment with a prevalent left-hemispheric vulnerability, and that LC degeneration might be linked to large-scale functional network alteration in AD pathology.

Biological determinants of blood-based cytokines in the Alzheimer's disease clinical continuum.

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1ß was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.

Norepinephrine Protects against Methamphetamine Toxicity through ß2-Adrenergic Receptors Promoting LC3 Compartmentalization.

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.

Appropriate use of generic and branded antiseizure medications in epilepsy: Updated recommendations from the Italian League Against Epilepsy (LICE).

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.

A longitudinal study of polysomnographic variables in patients with mild cognitive impairment converting to Alzheimer's disease.

The main condition at increased risk of dementia is considered to be mild cognitive impairment. Mild cognitive impairment has been defined as a transitional state between normal aging and dementia, of which it may represent a prodrome. The aim of our study was to evaluate whether sleep variables (both conventional and microstructural ones) in subjects with mild cognitive impairment correlate with conversion to dementia. Nineteen subjects with amnestic mild cognitive impairment (mean age 68.5 ±â€…7.0 years) and 11 cognitively intact healthy elderly individuals (mean age 69.2 ±â€…12.6 years) underwent ambulatory polysomnography for the evaluation of nocturnal sleep architecture and cyclic alternating pattern parameters. Amnestic mild cognitive impairment subjects were clinically and cognitively re-evaluated after 2 years, during routine follow-up, and further classified as amnestic mild cognitive impairment converters (that is, patients developing Alzheimer's disease, N = 11) and amnestic mild cognitive impairment non-converters. Compared with healthy elderly individuals, amnestic mild cognitive impairment showed disrupted sleep with decreased rapid eye movement sleep, cyclic alternating pattern rate and cyclic alternating pattern slow-wave-related phases (A1 index). Standard sleep architecture analysis did not show significant differences between the two subgroups of amnestic mild cognitive impairment, whereas cyclic alternating pattern analysis showed that cyclic alternating pattern rate, A1 index and A3 index are significantly reduced in converters compared with non-converters. Our data confirm that in amnestic mild cognitive impairment subjects there is a sleep impairment, particularly when considering more refined sleep parameters and that sleep variables at baseline are different among converters versus non-converters at the 2-year follow-up. Specific sleep alterations might represent potential further biomarkers for the diagnosis and prognosis of early-phase cognitive impairment.

Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus.

Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.

A companion to the preclinical common data elements and case report forms for rodent EEG studies. A report of the TASK3 EEG Working Group of the ILAE/AES Joint Translational Task Force.

Electroencephalography (EEG) is commonly used in epilepsy and neuroscience research to study brain activity. The principles of EEG recording such as signal acquisition, digitization, and conditioning share similarities between animal and clinical EEG systems. In contrast, preclinical EEG studies demonstrate more variability and diversity than clinical studies in the types and locations of EEG electrodes, methods of data analysis, and scoring of EEG patterns and associated behaviors. The TASK3 EEG working group of the International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force has developed a set of preclinical common data elements (CDEs) and case report forms (CRFs) for recording, analysis, and scoring of animal EEG studies. This companion document accompanies the first set of proposed preclinical EEG CRFs and is intended to clarify the CDEs included in these worksheets. We provide 7 CRF and accompanying CDE modules for use by the research community, covering video acquisition, electrode information, experimental scheduling, and scoring of EEG activity. For ease of use, all data elements and input ranges are defined in supporting Excel charts (Appendix S1).

The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer's Disease.

Alzheimer's Disease (AD) features the accumulation of ß-amyloid and Tau aggregates, which deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected during AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal relationship between these events. In the present mini-review, we dedicate special emphasis to those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we considered which molecular mechanism may render these brainstem neurons so vulnerable.

Loud Noise Exposure Produces DNA, Neurotransmitter and Morphological Damage within Specific Brain Areas.

Exposure to loud noise is a major environmental threat to public health. Loud noise exposure, apart from affecting the inner ear, is deleterious for cardiovascular, endocrine and nervous systems and it is associated with neuropsychiatric disorders. In this study we investigated DNA, neurotransmitters and immune-histochemical alterations induced by exposure to loud noise in three major brain areas (cerebellum, hippocampus, striatum) of Wistar rats. Rats were exposed to loud noise (100 dBA) for 12 h. The effects of noise on DNA integrity in all three brain areas were evaluated by using Comet assay. In parallel studies, brain monoamine levels and morphology of nigrostriatal pathways, hippocampus and cerebellum were analyzed at different time intervals (24 h and 7 days) after noise exposure. Loud noise produced a sudden increase in DNA damage in all the brain areas under investigation. Monoamine levels detected at 7 days following exposure were differently affected depending on the specific brain area. Namely, striatal but not hippocampal dopamine (DA) significantly decreased, whereas hippocampal and cerebellar noradrenaline (NA) was significantly reduced. This is in line with pathological findings within striatum and hippocampus consisting of a decrease in striatal tyrosine hydroxylase (TH) combined with increased Bax and glial fibrillary acidic protein (GFAP). Loud noise exposure lasting 12 h causes immediate DNA, and long-lasting neurotransmitter and immune-histochemical alterations within specific brain areas of the rat. These alterations may suggest an anatomical and functional link to explain the neurobiology of diseases which prevail in human subjects exposed to environmental noise.

Social cognition in Juvenile Myoclonic Epilepsy.

OBJECTIVE: Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome. Several studies have detailed cognitive and imaging abnormalities pointing to frontal lobe dysfunction, as well as disadvantageous behavioral traits and poor social outcome, challenging the commonly held view of JME being a benign disorder. Social cognition is the ability to elaborate mental representations of social interactions and to use them correctly in social contexts, and includes Theory of Mind (ToM), which pertains to the attribution of cognitive and affective mental states to self and others and seems to rely on complex fronto-temporal interactions. ToM has been recently assessed in focal epilepsy syndromes, but little is available for generalized epilepsies. We performed a cross-sectional study to assess social cognition, with an emphasis on ToM, as well as standard cognitive functions in patients with JME. METHOD: We recruited twenty JME patients and twenty matched controls. Tests used to assess social cognition and ToM included the Emotion Attribution Task, Strange Stories Task (SST), Faux Pas Task (FPT), Reading the Mind in the Eyes Task and Social Situation Task. Subjects were also assessed via an extensive neuropsychological battery. RESULTS: Patients exhibited worse performance in the SST and in several scores of the FPT. They also showed widespread cognitive impairment, involving executive functions, psychomotor speed, verbal and visuo-spatial memory. CONCLUSIONS: In addition to cognitive impairment for fronto-temporal tasks, some features of social cognition are also altered in JME. The latter deficit may underlie the poor social outcome previously described for these patients, and might also relate to imaging findings of frontal lobe dysfunction.

Novel MTCYB mutation in a young patient with recurrent stroke-like episodes and status epilepticus.

The acronym "MELAS" (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) denotes patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Here we report on a girl with repeated stroke-like episodes and status epilepticus, who was diagnosed with MELAS due to a novel mitochondrial cytochrome b gene (MTCYB) mutation (m.15092G>A, which predicts p.G116S). Western blotting and in silico analyses suggested that this mutation could affect the stability of complex III. Cytochrome b is the only mtDNA-encoded subunit of respiratory chain complex III. Mutations in MTCYB have been associated with isolated mitochondrial myopathy and exercise intolerance, and rarely with multisystem and/or central nervous system involvement. If the m.3243A>G and other common MELAS mutations are absent in several tissues, MTCYB should be sequenced from muscle in patients with stroke-like episodes, especially if muscle histology does not support a mitochondrial myopathy and lactic acidosis is absent.

A Clinical-EEG Study of Sleepiness and Psychological Symptoms in Pharmacoresistant Epilepsy Patients Treated with Lacosamide.

Our aim was to evaluate the EEG and clinical modifications induced by the new antiepileptic drug lacosamide (LCM) in patients with epilepsy. We evaluated 10 patients affected by focal pharmacoresistant epilepsy in which LCM (mean 250 mg/day) was added to the preexisting antiepileptic therapy, which was left unmodified. Morning waking EEG recording was performed before (t0) and at 6 months (t1) after starting LCM. At t0 and t1, patients were also administered questionnaires evaluating mood, anxiety, sleep, sleepiness, and fatigue (Beck Depression Inventory; State-Trait Anxiety Inventory Y1 and Y2; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Fatigue Severity Scale). We performed a quantitative analysis of EEG interictal abnormalities and background EEG power spectrum analysis. LCM as an add-on did not significantly affect anxiety, depression, sleepiness, sleep quality, and fatigue scales. Similarly, adding LCM to preexisting therapy did not modify significantly patient EEGs in terms of absolute power, relative power, mean frequency, and interictal abnormalities occurrence. In conclusion, in this small cohort of patients, we confirmed that LCM as an add-on does not affect subjective parameters which play a role, among others, in therapy tolerability, and our clinical impression was further supported by evaluation of EEG spectral analysis.

Daytime sleepiness in de novo untreated patients with epilepsy.

The aims of our study were to evaluate excessive daytime sleepiness in a group of de novo untreated people with epilepsy using a comprehensive and standardized approach, including subjective evaluation and neurophysiological and performance tests, and to compare these results with those obtained in a control group. Forty-seven patients with epilepsy (17 affected by primary generalized epilepsy and 30 by partial epilepsy), with a new epilepsy diagnosis and never treated, and 44 controls underwent Multiple Sleep Latency Test (preceded by nocturnal polysomnography), simple/complex visual reaction times, and Epworth Sleepiness Scale evaluation. Newly diagnosed and drug-free patients with epilepsy did not differ from controls in any of the tests performed to evaluate daytime sleepiness. In clinical practice, daytime sleepiness is a well-known and frequent complaint of patients with epilepsy, but different mechanisms and causes, such as associated psychiatric or sleep disorders, nocturnal seizures, sleep fragmentation, and antiepileptic drugs, must be taken into account. Excessive daytime sleepiness should not be considered an unavoidable consequence of epilepsy. Thus, a complete diagnostic work-up in patients with epilepsy and sleepiness should be undertaken whenever possible.

The effects of locus coeruleus and norepinephrine in methamphetamine toxicity.

The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters.

Usefulness of a simple sleep-deprived EEG protocol for epilepsy diagnosis in de novo subjects.

OBJECTIVE: In case series concerning the role of EEG after sleep deprivation (SD-EEG) in epilepsy, patients' features and protocols vary dramatically from one report to another. In this study, we assessed the usefulness of a simple SD-EEG method in well characterized patients. METHODS: Among the 963 adult subjects submitted to SD-EEG at our Center, in the period 2003-2010, we retrospectively selected for analysis only those: (1) evaluated for suspected epileptic seizures; (2) with a normal/non-specific baseline EEG; (3) still drug-free at the time of SD-EEG; (4) with an MRI analysis; (5) with at least 1 year follow-up. SD-EEG consisted in SD from 2:00 AM and laboratory EEG from 8:00 AM to 10:30 AM. We analyzed epileptic interictal abnormalities (IIAs) and their correlations with patients' features. RESULTS: Epilepsy was confirmed in 131 patients. SD-EEG showed IIAs in 41.2% of all patients with epilepsy, and a 91.1% specificity for epilepsy diagnosis; IIAs types observed during SD-EEG are different in generalized versus focal epilepsies; for focal epilepsies, the IIAs yield in SD-EEG is higher than in second routine EEG. CONCLUSIONS: This simple SD-EEG protocol is very useful in de novo patients with suspected seizures. SIGNIFICANCE: This study sheds new light on the role of SD-EEG in specific epilepsy populations.

Fabry disease with atypical neurological presentation: report of a case.

INTRODUCTION: Fabry disease (FD) is a rare, X-linked lysosomal storage disorder with multiorgan involvement. FD is caused by a partial or total deficit of α-galactosidase A enzyme, which is responsible for the accumulation of glycosphingolipids in a variety of cell types. Neurological complications include central nervous system involvement with cerebrovascular disease, peripheral neuropathy, and autonomic dysfunction. CASE REPORT: We report the case of a 47-year-old man with an atypical neurological presentation of FD, characterized by 48-hour consciousness alteration with amnesia, resembling a long-lasting episode of transient global amnesia. CONCLUSIONS: Our case expands the neurological presentations associated with FD.

The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation.

Stimulation of the vagus nerve produces antiepileptic effects. This is used clinically to treat drug-refractory epilepsies. The mechanisms responsible for these effects depend on the activation of vagal afferents reaching the nucleus of the solitary tract. This review focuses on the neuroanatomy of the nucleus of the solitary tract and its relation with the nucleus locus coeruleus as a preferential anatomical substrate in producing antiepileptic effects. In fact, following the transient or permanent inactivation of locus coeruleus neurons, some antiepileptic effects of vagus nerve stimulation are lost. The activation of locus coeruleus per se is known to limit the spread of a seizure and the duration of a variety of seizure types. This is due to the fine chemical neuroanatomy of norepinephrine pathways that arise from the locus coeruleus, which produce widespread changes in cortical areas. These changes may be sustained by norepinephrine alone, or in combination with its co-transmitters. In addition, vagus nerve stimulation may prevent seizures by activating the serotonin-containing dorsal raphe neurons.

The chemical neuroanatomy of vagus nerve stimulation.

In this short overview a reappraisal of the anatomical connections of vagal afferents is reported. The manuscript moves from classic neuroanatomy to review details of vagus nerve anatomy which are now becoming more and more relevant for clinical outcomes (i.e. the therapeutic use of vagus nerve stimulation). In drawing such an updated odology of central vagal connections the anatomical basis subserving the neurochemical effects of vagal stimulation are addressed. In detail, apart from the thalamic projection of central vagal afferents, the monoaminergic systems appear to play a pivotal role. Stemming from the chemical neuroanatomy of monoamines such as serotonin and norepinephrine the widespread effects of vagal stimulation on cerebral cortical activity are better elucidated. This refers both to the antiepileptic effects and most recently to the beneficial effects of vagal stimulation in mood and cognitive disorders.