In the past, little or no attention was paid to cognitive disorders associated with depression (a condition sometimes termed pseudodementia). However, recent years have seen a growing interest in these changes, not only because of their high frequency in acute-stage depression, but also because they have been found to persist, as residual symptoms (in addition to affective and psychomotor ones), in many patients who respond well to antidepressant treatment. These cognitive symptoms seem to impact significantly not only on patients’ functioning and quality of life, but also on the risk of recurrence of depression. Therefore, over the past decade, pharmacological research in this field has focused on the development of new agents able to counteract not only depressive symptoms, but also cognitive and functional ones. In this context, novel antidepressants with multimodal activity have emerged. This review considers the different issues, in terms of disease evolution, raised by the presence of cognitive disorders associated with depression and considers, particularly from the neurologist’s perspective, the ways in which the clinical approach to cognitive symptoms, and their interpretation to diagnostic and therapeutic ends, have changed in recent years. Finally, after outlining the pharmacodynamics and pharmacokinetics of the first multimodal antidepressant, vortioxetine, it reports the main results obtained with the drug in depressed patients, also in consideration of the ever-increasing evidence on its different mechanisms of action in animal models.

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.

Alzheimer disease (AD) and vascular dementia (VaD) together represent the majority of dementia cases. Since their neuropsychological profiles often overlap and white matter lesions are observed in elderly subjects including AD, differentiating between VaD and AD can be difficult. Characterization of these different forms of dementia would benefit by identification of quantitative imaging biomarkers specifically sensitive to AD or VaD. Parameters of microstructural abnormalities derived from diffusion tensor imaging (DTI) have been reported to be helpful in differentiating between dementias, but only few studies have used them to compare AD and VaD with a voxelwise approach. Therefore, in this study a whole brain statistical analysis was performed on DTI data of 93 subjects (31 AD, 27 VaD, and 35 healthy controls—HC) to identify specific white matter patterns of alteration in patients affected by VaD and AD with respect to HC. Parahippocampal tracts were found to be mainly affected in AD, while VaD showed more spread white matter damages associated with thalamic radiations involvement. The genu of the corpus callosum was predominantly affected in VaD, while the splenium was predominantly affected in AD revealing the existence of specific patterns of alteration useful in distinguishing between VaD and AD. Therefore, DTI parameters of these regions could be informative to understand the pathogenesis and support the etiological diagnosis of dementia. Further studies on larger cohorts of subjects, characterized for brain amyloidosis, will allow to confirm and to integrate the present findings and, furthermore, to elucidate the mechanisms of mixed dementia. These steps will be essential to translate these advances to clinical practice.

Background and Aims: Neurogenic dysphagia linked to failed relaxation of the upper esophageal sphincter (UES) can be treated by injecting botulinum toxin (BTX) into the cricopharyngeal (CP) muscle. We compared the effects of this treatment in different neurological disorders with dysphagia, to evaluate its efficacy over time including the response to a second injection. Materials and Methods: Sixty-seven patients with neurogenic dysphagia associated with incomplete or absent opening of the UES (24 with brainstem or hemispheric stroke, 21 with parkinsonian syndromes, 12 with multiple sclerosis, and 10 with spastic-dystonic syndromes secondary to post-traumatic encephalopathy) were treated with the injection of IncobotulinumtoxinA (dose 15–20 U) into the CP muscle under electromyographic guidance. The patients were assessed at baseline and after the first and second treatment through clinical evaluation and fiberoptic endoscopy of swallowing, while their dysphagia was quantified using the Dysphagia Outcome and Severity Scale (DOSS). An electrokinesiographic/electromyographic study of swallowing was performed at baseline. Results: Most patients responded to the first BTX treatment: 35 patients (52.2%) were classified as high responders (DOSS score increase >2 levels), while other 19 patients (28.4%) were low responders (DOSS score increase of ≤2 levels). The effect of the first treatment usually lasted longer than 4 months (67%), and in some cases up to a year. The treatment efficacy remained high also after the second injection: 31 patients (46.3%) qualified as high responders and other 22 patients (32.8%) showed a low response. Only in the parkinsonian syndromes group we observed a reduction in the percentage of high responders as compared with the first treatment. Side effects were mostly mild and reported in non-responders following the first injection. A severe side effect, consisting of ingestion pneumonia, was observed following the second BTX injection in two patients who had both been non-responders to the first. Non-responders were characterized electromyographically by higher values of the oropharyngeal interval. Conclusion: These findings confirm the effectiveness of IncobotulinumtoxinA injection in the treatment of neurogenic dysphagia due to hyperactivity and relaxation failure of the UES. Caution should be used as regards, the re-injection in non-responders to the first treatment.

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches including cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Another form, hemicrania continua (HC), is also included this group due to its clinical and pathophysiological similarities. CH is the most common of these syndromes, the others being infrequent in the general population. The pathophysiology of the TACs has been partly elucidated by a number of recent neuroimaging studies, which implicate brain regions associated with nociception (pain matrix). In addition, the hypothalamic activation observed in the course of TAC attacks and the observed efficacy of hypothalamic neurostimulation in CH patients suggest that the hypothalamus is another key structure. Hypothalamic activation may indeed be involved in attack initiation, but it may also lead to a condition of central facilitation underlying the recurrence of pain episodes. The TACs share many pathophysiological features, but are characterised by differences in attack duration and frequency, and to some extent treatment response. Although alternative strategies for the TACs, especially CH, are now emerging (such as neurostimulation techniques), this review focuses on the available pharmacological treatments complying with the most recent guidelines. We discuss the clinical efficacy and tolerability of the currently used drugs. Due to the low frequency of most TACs, few randomised controlled trials have been conducted. The therapies of choice in CH continue to be the triptans and oxygen for acute treatment, and verapamil and lithium for prevention, but promising results have recently been obtained with novel modes of administration of the triptans and other agents, and several other treatments are currently under study. Indomethacin is extremely effective in PH and HC, while antiepileptic drugs (especially lamotrigine) appear to be increasingly useful in SUNCT. We highlight the need for appropriate studies investigating treatments for these rare, but lifelong and disabling conditions.

Background: Trigeminal neuralgia (TN) is a severe, disabling form of painful cranial neuropathy. Even though TN has a typical clinical picture, diagnosis it is often missed or delayed in clinical practice. In order to investigate the occurrence of diagnostic and therapeutic errors in TN, we studied 102 patients suffering from TN recruited through a multicentric survey. Methods: We performed a Pubmed database search on errors and pittfalls in TN diagnosis and management. Then, patients with TN were consecutively enrolled in the period from February 2017 to October 2019, by several European Headache Centers participating in the study, following a call of the Headache and Pain Scientific Panels of the European Academy of Neurology (EAN). Diagnosis of Classical Trigeminal Neuralgia (CTN) was made according to the International Headache Society (IHS) criteria (Tölle et al., Pain Pract 6:153-160, 2006). All the patients were evaluated using telephone/frontal interviews conducted by headache/pain specialists using an ad hoc questionnaire. Results: A number of 102 patients were recruited, mostly females (F:M ratio 2.64:1). Eighty-six percent of the patients consulted a physician at the time they experienced the first pain attacks. Specialists consulted before TN diagnosis were: primary care physicians (PCP) (43.1%), dentists (in 30.4%), otorhinolaryngologists (3.9%), neurosurgeons (3.9%), neurologists or headache specialists (14.7%), others (8%). The final diagnosis was made mainly by a neurologist or headache specialist (85.3%), and the mean interval between the disease onset and the diagnosis made by a specialist was 10.8 ± 21.2 months. The “diagnostic delay” was 7.2 ± 12.5 months, and misdiagnoses at first consultation were found in 42.1% of cases. Instrumental and laboratory investigations were carried out in 93.1% of the patients before the final diagnosis of TN. Conclusion: While TN has typical features and it is well defined by the available international diagnostic criteria, it is still frequently misdiagnosed and mistreated. There is a need to improve the neurological knowledge in order to promptly recognize the clinical picture of TN and properly adhere to the specific guidelines. This may result in a favorable outcome for patients, whose quality of life is usually severely impaired.