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Cognitive performance in Major Depressive Disorder (MDD) is frequently impaired and related to functional outcomes. Repetitive Transcranial Magnetic Stimulation (rTMS) may exert its effects on MDD acting both on depressive symptoms and neurocognition. Furthermore, cognitive status could predict the therapeutic response of depressive symptoms to rTMS. However, cognitive performances as a predictor of rTMS response in MDD has not been thoroughly investigated. This review aims to evaluate the role of pre-treatment cognitive performance as a predictor of clinical response to rTMS, and the effects of rTMS on neurocognition in MDD.A systematic review of studies evaluating neurocognition in MDD as an outcome and/or predictor of response to rTMS was conducted using PubMed/Medline and Embase.Fifty-eight articles were identified: 25 studies included neurocognition as a predictor of response to rTMS; 56 used cognitive evaluation as an outcome of rTMS. Baseline cognitive performance and cognitive improvements after rTMS predicted clinical response to rTMS. Moreover, rTMS improved cognition in MDD.Cognitive assessment could predict improvement of depression in MDD patients undergoing rTMS and help selecting patients that could have beneficial effects from rTMS. A routine cognitive assessment might stratify MDD patients and track rTMS related cognitive improvement.

To investigate the potential contributions of diastolic and systolic blood pressure (BP) and the circadian rhythm of BP to chronic migraine evolution.This cross-sectional study included four groups of patients selected based on migraine frequency (high frequency ≥ 10 days per month and low frequency10) and on the presence of hypertension. Among-group and pairwise comparisons were carried out to investigate potential neurophysiologic differences in the cerebral vessel reactivity to a nitroglycerin test, in autonomic balance (tilting test), and BP circadian rhythm.A more marked decrease in cerebral blood flow velocity was observed in hypertensive high-frequency migraineurs compared to all other groups (P = .037). Moreover, a smaller decrease in vagal tone was recorded in the orthostatic position in hypertensive subjects, whether they were high- (P = .032) or low-frequency migraineurs (P = .014), with a consistently higher vagal to sympathetic tone ratio (P = .033). Finally, in nonhypertensive subjects, a higher but not significant prevalence of systolic nondippers was detected in high-frequency migraineurs (67%) compared to low-frequency subjects (25%; P = .099).These findings suggest that hypertension may contribute to the chronic evolution of headache with mechanisms shared with migraine; ie, vascular tone alteration and autonomic dysregulation.

Background: Evidence suggests increased anxious-depressive symptoms in the general population during the COVID-19 pandemic, also in its second wave. High symptom variability across individuals suggests that risk and protective factors, including coping strategies, can play a mediating role. Methods: General Anxiety Disorder-7, Patient Health Questionnaire-9, and Brief-COPE questionnaires were administered to people attending a COVID-19 point-of-care. Univariate and multivariate methods were used to test the association of symptoms with risk and protective factors. Results: A total of 3509 participants (27.5% with moderate-severe anxiety; 12% with depressive symptoms) were recruited. Sociodemographic and lifestyle factors, including age, sex, sleep, physical activity, psychiatric treatments, parenthood, employment, and religiosity were associated with affective symptoms. Avoidant (self-distraction, venting, behavioral disengagement) and approach (emotional support, self-blame but not positive reframing and acceptance) coping strategies predicted greater anxiety. Avoidant strategies, including venting, denial, behavioral disengagement, substance use, and self-blame, and the humor strategy were associated with more severe depressive symptoms, while the planning predicted the opposite. Conclusions: Coping strategies, in addition to socio-demographic and life-habit factors, could have contributed to modulating anxious and depressive symptoms during the second-wave of the COVID-19 pandemic, thus advocating for interventions aimed at promoting positive coping strategies to reduce the psychosocial toll of the pandemic.

A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor necrosis factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of four case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600-0.53% - experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.

Neurofilament light chains (NfL) are neuron-specific cytoskeletal proteins whose plasmatic concentrations have been explored as a clinically useful marker in several types of dementia. Plasma concentrations of NfL are extremely low, and just two assays are commercially available for their study: one based on the SiMoA™ technology and one based on Ella™. We thus studied plasma levels of NfL with both platforms to check the correlation between them and to assess their potential in the diagnosis of dementia. Plasma NfL levels were measured on 50 subjects: 18 healthy controls, 20 Alzheimer’s disease, and 12 frontotemporal dementia patients. Ella™ returned plasmatic NfL levels significantly higher than SiMoA™, however the results were strongly correlated (r = 0.94), and a proportional coefficient of 0.58 between the two assays was calculated. Both assays detected higher plasma NfL levels in patients with dementia than in the control group (p 0.95). No difference was found between Alzheimer’s and Frontotemporal dementia either using SiMoA™ or Ella™. In conclusion, both the analytical platform resulted effective in analysing plasma levels of NfL. However, the correct interpretation of results requires the precise knowledge of the assay used.

Un caso clinico di corea in paziente con iperglicemia non chetoacidosica e infezione da SARS-Cov-2

Purpose To review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis. Methods Systematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment. Results Thirty-two studies were eligible. (a) Outcome categories were clinician-centered (found in 25/32 studies, 78%), patient-/caregiver-centered (in 9/32 studies, 28%), and health economics-centered (5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients’ outcomes (n = 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection. Conclusion Current studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.

Growing evidence supports the presence of social cognition deficits and social behavior alterations in major and minor neurocognitive disorders (NCDs). Even though the ability to identify socio-emotional changes has significantly improved in recent years, there is still no specific treatment available. Thus, we explored evidence of drug therapies targeting social cognition alterations in NCDs. Papers were selected according to PRISMA guidelines by searching on the PubMed and Scopus databases. Only papers reporting information on pharmacological interventions for the treatment of social cognition and/or social behavioral changes in major and/or minor NCDs were included. Among the 171 articles entered in the paper selection, only 9 papers were eligible for the scope of the review. Trials testing pharmacological treatments for socio-emotional alterations in NCDs are poor and of low-medium quality. A few attempts with neuroprotective, psychoactive, or immunomodulating drugs have been made. Oxytocin is the only drug specifically targeting the social brain that has been tested with promising results in frontotemporal dementia. Its beneficial effects in long-term use have yet to be evaluated. No recommendation can currently be provided. There is a long way to go to identify and test effective targets to treat social cognition changes in NCDs for the ultimate benefit of patients and caregivers.

Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant.Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events.The VNS implant was associated with a sustained response (10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred.Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Purpose To assess the clinical impact and incremental diagnostic value of 18F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis. Methods The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions. Results FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia “of unclear etiology” (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer’s disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p 5 and Conclusion Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia.

Cerebrospinal fluid (CSF) amino acid (AA) levels and CSF/plasma AA ratios in Alzheimer Disease (AD) in relation to nutritional state are not known. Methods: In 30 fasting patients with AD (46% males, 74.4 ± 8.2 years; 3.4 ± 3.2 years from diagnosis) and nine control (CTRL) matched subjects, CSF and venous blood samples were drawn for AA measurements. Patients were stratified according to nutritional state (Mini Nutritional Assessment, MNA, scores). Results: Total CSF/plasma AA ratios were lower in the AD subpopulations than in NON-AD (p < 0.003 to 0.017. In combined malnourished (16.7%; MNA < 17) and at risk for malnutrition (36.6%, MNA 17–24) groups (CG), compared to CTRL, all essential amino acids (EAAs) and 30% of non-EAAs were lower (p < 0.018 to 0.0001), whereas in normo-nourished ADs (46.7%, MNA > 24) the CSF levels of 10% of EAAs and 25% of NON-EAAs were decreased (p < 0.05 to 0.00021). CG compared to normo-nourished ADs, had lower CSF aspartic acid, glutamic acid and Branched-Chain AA levels (all, p < 0.05 to 0.003). CSF/plasma AA ratios were

Cerebrospinal fluid (CSF) amino acid (AA) levels and CSF/plasma AA ratios in Alzheimer Disease (AD) in relation to nutritional state are not known. Methods: In 30 fasting patients with AD (46% males, 74.4 ± 8.2 years; 3.4 ± 3.2 years from diagnosis) and nine control (CTRL) matched subjects, CSF and venous blood samples were drawn for AA measurements. Patients were stratified according to nutritional state (Mini Nutritional Assessment, MNA, scores). Results: Total CSF/plasma AA ratios were lower in the AD subpopulations than in NON-AD (p < 0.003 to 0.017. In combined malnourished (16.7%; MNA < 17) and at risk for malnutrition (36.6%, MNA 17–24) groups (CG), compared to CTRL, all essential amino acids (EAAs) and 30% of non-EAAs were lower (p < 0.018 to 0.0001), whereas in normo-nourished ADs (46.7%, MNA > 24) the CSF levels of 10% of EAAs and 25% of NON-EAAs were decreased (p < 0.05 to 0.00021). CG compared to normo-nourished ADs, had lower CSF aspartic acid, glutamic acid and Branched-Chain AA levels (all, p < 0.05 to 0.003). CSF/plasma AA ratios were

Background: Bisdemethoxycurcumin (BDC) might be an inflammation inhibitor in Alzheimer’s Disease (AD). However, BDC is almost insoluble in water, poorly absorbed by the organism, and degrades rapidly. We thus developed a new nanoformulation of BDC based on H-Ferritin nanocages (BDC-HFn). Methods: We tested the BDC-HFn solubility, stability, and ability to cross a blood–brain barrier (BBB) model. We tested the effect of BDC-HFn on AD and control (CTR) PBMCs to evaluate the transcriptomic profile by RNA-seq. Results: We developed a nanoformulation with a diameter of 12 nm to improve the solubility and stability. The comparison of the transcriptomics analyses between AD patients before and after BDC-HFn treatment showed a major number of DEG (2517). The pathway analysis showed that chemokines and macrophages activation differed between AD patients and controls after BDC-HFn treatment. BDC-HFn binds endothelial cells from the cerebral cortex and crosses through a BBB in vitro model. Conclusions: Our data showed how BDC-Hfn could improve the stability of BDC. Significant differences in genes associated with inflammation between the same patients before and after BDC-Hfn treatment have been found. Inflammatory genes that are upregulated between AD and CTR after BDC-HFn treatment are converted and downregulated, suggesting a possible therapeutic approach.

BackgroundBehavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field.MethodsA multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects.ResultsOne-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings.ConclusionThe survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need.

Limbic encephalitis is an inflammatory process of the limbic structures, with polymorphic clinical features, caused by paraneoplastic and nonparaneoplastic conditions and infections. We describe a case of neurosyphilis limbic encephalitis, presenting with reversible Geschwind syndrome (hyperreligiosity and hypergraphia) and mood disorder due to the predominant involvement of left mesial temporal structures in a previously healthy 34-year-old, left-handed woman. Because neurosyphilis can mimic common neuropsychiatric syndromes, it should be included in the differential diagnosis of psychiatric disorders with suspected general medical causes. This case of nondominant limbic encephalopathy caused by syphilis infection highlights the relevance of a careful investigation for secondary psychotic, mood, and personality disorders when assessing new-onset psychiatric illness and the importance of a multidisciplinary approach to provide a better outcome in patients with neurosyphilis.

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.

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

BACKGROUND Previous studies have suggested that evening intake of benzodiazepine affects blood pressure (BP) and/or heart rate (HR) in healthy and hypertensive subjects. The aim of this study was to compare the effect of chronic oral administration of alprazolam and lorazepam as hypnotics on ambulatory BP and HR in patients with mild hypertension. METHODS Consecutive outpatients of both sexes with newly diagnosed, never-treated mild hypertension were randomized, after a 4-week placebo run-in period, to receive alprazolam 0.5 mg plus placebo, lorazepam 1 mg plus placebo, or placebo plus placebo for 2 weeks in 3 crossover periods, each separated by a 1-week placebo wash-out period. At the end of the initial placebo run-in and of each treatment period, 24-hour ambulatory BP and HR monitoring was performed using a noninvasive device. RESULTS In the 32 patients, no treatment had any effect on 24-hour and daytime systolic BP (SBP), diastolic BP (DBP), and HR, which remained unchanged. During the nighttime, SBP and DBP values were unaffected by alprazolam, as compared with placebo, whereas DBP was significantly higher after treatment with lorazepam (+3.7%, P < 0.05 vs placebo). Nocturnal HR mean values were significantly increased by lorazepam (+10.1%, P < 0.01 vs placebo), whereas they did not change after alprazolam. CONCLUSIONS In patients with mild hypertension, oral intake of alprazolam or lorazepam as hypnotics did not affect ambulatory BP or HR values. A slight increase in nighttime DBP was observed with lorazepam, whereas alprazolam showed no effect on nocturnal BP and HR, probably reflecting a stimulating effect of the drug on central α2-receptors.

Objectives Autoimmune encephalitis due to antibodies against neuronal surface antigens (NSA-Ab) frequently presents with cognitive impairment, often as the first and prevalent manifestation, but few studies have systematically assessed the frequency of NSA-Ab in consecutive patients with established neurodegenerative disorders. Methods We studied sera of 93 patients (41F, 52 M), aged 69.2 ± 9.4 years, with neurodegenerative conditions, and of 50 population controls aged over 60 years. Specific NSA-Abs were investigated by antigen-specific cell-based assays (CBAs). After testing, we evaluated the association between the NSA-Abs and clinical, CSF and radiological features. Results The patients included 13/93 (13.8%) who had specific antibodies to neuronal surface antigens: 6 GlyR, 3 GABAAR (1 also positive for AMPAR), 2 LGI1, 1 CASPR2 and 1 GABABR. One of the 50 controls (2%) was positive for NMDAR antibody and the others were negative on all tests (P = 0.020). No difference was observed in antibody frequency between patients presenting with parkinsonism and those presenting with dementia (P = 0.55); however, NSA-Ab were more frequent in those with unclassified forms of dementia (5/13, 38.5%) than in those with unclassified parkinsonism (2/9, 22.2%) or with classified forms of dementia (4/43, 9.3%) or parkinsonism (2/28, 7.1%) (P = 0.03). A logistic regression analysis demonstrated that an unclassified diagnosis (P = 0.02) and an irregular progression (P = 0.024) were predictors of seropositive status. Conclusions NSA-Abs are relatively frequent in patients with neurodegenerative disorders, particularly in those with an irregular disease progression of atypical clinical features, inconsistent with a recognized diagnosis. The significance of these antibodies and their possible primary or secondary roles need to be investigated in prospective studies.

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

BackgroundIdentifying robust 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 mRNA/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.MethodsLEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and ultracentrifugation and RNA was extracted. Whole transcriptome and miRNA libraries were carried out by Next Generation Sequencing (NGS).ResultsWe detected different deregulated RNAs in LEVs and SEVs from patients with the same disease. MiRNAs resulted to be the most interesting subpopulation of transcripts transported by plasma derived SEVs since they appeared to discriminate all NDs disease from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were mainly linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway.ConclusionLEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading/protection of the disease. The study of common and different RNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.

Aim: To assess the effects of chronic evening oral administration of bromazepam alone or in combination with propranolol on ambulatory blood pressure (BP) and heart rate (HR) in mild hypertensive subjects. Methods: Thirty-seven mild hypertensive patients after a 2-week placebo period were randomized to bromazepam 3 mg, propranolol 40 mg, bromazepam 3 mg plus propranolol 40 mg or placebo for 2 weeks according to a double-blind, double dummy, cross-over design. After each treatment period, 24-h BP and HR ambulatory monitoring was performed by using a non-invasive device. Results: Ambulatory monitoring showed that during night-time SBP and DBP values were unaffected by bromazepam as compared to placebo, whereas SBP was significantly reduced by propranolol both when taken alone and in combination with bromazepam. HR nocturnal values were significantly reduced by propranolol, whereas they were significantly increased by bromazepan both when taken alone (+11.5%, p < 0.05 vs. placebo) and in combination with propranolol (+12.8%, p < 0.05 vs. propranolol). No significant difference in day-time values of SBP, DBP and HR was observed among the 4 treatment groups. Conclusions: In mild hypertensive patients, evening consumption of bromazepam for a 2-week period did not affect BP, while it increased nocturnal HR. Such an increase was observed both when bromazepam was taken alone and in combination with propranolol, which suggests that it depends on a bromazepam mediated decrease in vagal tone. Whatever the mechanism, the HR nocturnal increase might be of clinical relevance, due to the role of high HR as cardiovascular risk factor, particularly in already at risk hypertensive subjects.

The present study was carried out in order to assess the effects of chronic administration of flunitrazepam (as an oral hypnotic) on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. Following a 2-week placebo run-in period, 28 healthy volunteers (13 males and 15 females) between 21 and 30 years were randomized to receive either flunitrazepam 1 mg or placebo (both administered once a day in the evening) for 4 weeks in two cross-over periods; each separated by a 2-week placebo period. At the end of each study period, non-invasive 24-h BP and HR ambulatory monitoring was performed. Flunitrazepam produced a significant decrease in nighttime systolic blood pressure (SBP) (− 6.4 mmHg) and diastolic blood pressure (DBP) (− 4.1 mmHg) (both P

The use of biomarkers has recently supported the association between Alzheimer disease (AD) pathology and the logopenic variant of primary progressive aphasia (PPA). We aim to investigate possible differences in cerebrospinal fluid (CSF) biomarker concentrations in the three PPA variants, and to assess any agreement between CSF biomarkers and (18)F-florbetapir PET. A group of 10 PPA were retrospectively enrolled. Patients with logopenic variant (lvPPA) showed different levels of Aβ1-42 and p-tau compared to nonfluent/agrammatic and semantic variants (nfv/svPPA). All nfv/svPPA patients had negative amyloid PET. Among the lvPPA group, a negative amyloid PET was found only in one patient, who was also the only one to display a normal CSF. Thus, this small cohort appeared to display an excellent agreement between CSF and (18)F-florbetapir PET and suggest that these examinations may have the same validity in detecting in vivo evidence of AD pathology in PPA clinical variants.

Trigeminal autonomic cephalalgias (TACs) are primary headaches that include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks (SUNHAs) with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA). Hemicrania continua (HC) is another form that has been ascribed to TACs for clinical and pathophysiologic reasons. Cluster headache is the most common of these syndromes, even if comparatively rare, with a lifetime prevalence of around 1 in 1,000. TACs share many aspects from a pathophysiologic standpoint (a hypothalamic activation may be involved in all forms initiating the attacks), but differences in attack duration and frequency and in extent of treatment response distinguish one from the other. This review focuses on the treatments currently available for these headaches according to the most recent guidelines. Due to the low frequency of most TACs, there are little data from randomized controlled trials; therefore, evidence from simple open studies in small case series or single-case observations are reported. Promising results have been recently obtained with novel modes of drug administration, invasive pericranial interventions, and different strategies such as neurostimulation. There are also some future treatments being studied at present.

Alpha-PVP can be defined as a novel psychoactive substance (NPS)-more specifically, a novel synthetic cathinone with unpredictable stimulant effects in humans. "Marvin" arrived at a Dual Diagnosis Unit at Parco dei Tigli, Italy. He underwent a 30-day rehabilitation program to overcome his problematic Alpha-PVP use as a psychonaut. We conducted an online search to understand the properties of Alpha-PVP and its presence in scientific literature, reviewing official reports and the online drug market (e.g., fora, webpages). In the Dual Diagnosis Unit, Marvin completed the 30-day rehabilitation program that included assessments and group and individual cognitive behavioral therapy. Alpha-PVP is a synthetic cathinone with stimulant properties, available in the online market but with unpredictable effects in humans. The present case reports an important risk of psychosis in a psychonaut patient who arrived and declared its intense use before admission to our Unit. This article describes the psychopathological effects of the novel compound Alpha-PVP in a psychonaut patient. Patients attending clinics that have used Alpha-PVP pose a new challenge for traditional services of mental health and addiction.

No study has evaluated the cardiovascular effects of diazepam in elderly subjects that assume diazepam to induce sleep. The present study was carried out in order to evaluate the effects of chronic administration of diazepam as hypnotic drug on blood pressure (BP) and heart rate (HR) in healthy elderly subjects. Healthy, elderly subjects, aged 65–74 years, were treated with diazepam 5 mg or placebo—both administered once a day in the evening—for 4 weeks in two cross-over periods, each separated by a 2-week placebo period, according to a randomized, double-blind, cross-over design. At the end of each study period, clinical as well as 24-h ambulatory BP and HR were evaluated. A total of 25 subjects were included in the analysis. At the end of a 4-week diazepam treatment, clinical as well 24-h BP and HR mean values were not significantly affected. Analysis of sub-periods showed that during night-time, systolic BP (SBP) values under diazepam were 7.6% higher than under placebo, with a mean difference of 7.9 mmHg (p

Deep Brain Stimulation represents a therapeutic option for PD patients. In this paper, we present and discuss a case of acute delirium and psychosis manifesting after DBS in a 58-years-old man affected by Parkinson's Disease. We highlight the importance of an exhaustive psychiatric evaluation in candidates for DBS and we underline the severity and non-reversibility of some adverse events associated with the implantation, suggesting the use of Quetiapine in the management of these effects. Acute psychosis may be listed as a potential severe adverse event associated with DBS, even in patients without a clear cut previous history of psychiatric disorders.

Although parkinsonism is considered a core feature of dementia with Lewy bodies (DLB), it is occasionally mild or even absent. I-FP-CIT SPECT has been accepted as a diagnostic support tool in this context, given that low striatal uptake is associated with neuronal loss. The aim of this retrospective study was to look for correlations between I-FP-CIT uptake in the striatum and clinical extrapyramidal signs (EPSs) in patients with a diagnosis of probable DLB to clarify the extent to which the supporting role of I-FP-CIT is related to motor impairment.Semiquantitative I-FP-CIT uptake was analyzed and correlated with Unified Parkinson Disease Rating Scale Part III scores in a sample of 22 patients with a diagnosis of probable DLB and a wide range of EPSs.A significant negative linear correlation between I-FP-CIT uptake and Unified Parkinson Disease Rating Scale Part III score was found both in the caudate and the putamen (r = -0.69 and -0.72, respectively, P0.001). Striatal uptake in patients with no or questionable EPS was comparable to that recorded in normal age-matched subjects (99% [22%] in the putamen) but significantly reduced in those with mild and severe EPS (43% [35%] and 30% [17%], respectively, P0.0001, but P = nonsignificant between mild and severe EPS).SPECT may be redundant when there are no doubts about the parkinsonism (ie, when it is absent or unequivocally present), but it may be helpful in identifying presynaptic nigrostriatal degeneration in patients with mild EPSs.

Changes in hippocampal gray matter volumes are proposed to be involved in pathogenesis, course, and treatment response of major depressive disorder. Converging evidence suggests that reduced neurogenesis may occur in treatment-resistant depression (TRD). Vagus nerve stimulation (VNS) is a well-defined, long-term brain stimulation treatment for TRD. However, its in vivo positive effect on hippocampal modulation as mechanism of action has never been investigated before in clinical studies. In this study, we intended to explore hippocampal volumetric changes and clinical antidepressant responses in patients with TRD after 6 and 12 months of treatment with VNS.The TRD outpatients were evaluated for VNS implantation. Right and left hippocampal volumes in 6 TRD patients, who met the criteria for VNS treatment, were measured at baseline before the implantation and after 6 and 12 months. The patients were assessed using Beck Depression Inventory and Hamilton Depression Rating Scale at baseline and at follow-up visits.There was a statistically significant and progressive increase in right and left hippocampal volumes during the follow up (P0.05). Furthermore, patients showed a significant improvement on Hamilton Depression Rating Scale and Beck Depression Inventory scores (P0.05).Our data suggest a VNS modulatory effect on hippocampal plasticity as measured by hippocampal gray volume increase in TRD patients. These preliminary findings indicate the fundamental role of hippocampal remodeling as a marker of response to VNS in TRD.

Summary Neuroactive steroids modulate anxiety in experimental animals and possibly in humans. The secretion of these compounds has been found to be altered in panic disorder (PD), with such alterations having been suggested to be a possible cause or effect of panic symptomatology. Panic-like attacks can be induced in healthy individuals by administration of panicogenic agents or by physical procedures, and we have now measured the plasma concentrations of neuroactive steroids in such individuals before, during, and after panicogenic inhalation of CO2 in order to investigate whether abnormalities of neuroactive steroid secretion might contribute to the pathogenesis of PD. Fifty-nine psychologically and physically healthy subjects, including 42 women (11 in the follicular phase of the menstrual cycle, 14 in the luteal phase, and 17 taking contraceptive pills) and 17 men, who experienced a panic-like attack on previous exposure to 7% CO2 were again administered 7% CO2 for 20 min. Thirty-three of these individuals (responders) again experienced a panic-like attack, whereas the remaining 26 subjects did not (nonresponders). All subjects were examined with the VAS-A and PSL-III-R scales for anxiety and panic symptomatology before and after CO2 inhalation. The plasma concentrations of progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THPROG = allopregnanolone), 3α,5α-tetrahydrodesoxycorticosterone (3α,5α-THDOC), dehydroepiandrosterone (DHEA), and cortisol were measured 15 min and immediately before the onset of CO2 administration as well as immediately, 10, 30, and 50 min after the end of CO2 inhalation. Neuroactive steroids were measured in the laboratory of Prof. Biggio in Cagliari, Sardinia, Italy. Neurosteroid levels did not change significantly in both responders and nonresponders before, during, or after CO2 inhalation. These data suggest that neuroactive steroid concentrations before, during, or after CO2 inhalation do not seem to correlate with panic symptomatology during panic-like attacks in subjects not affected by PD, and they therefore do not support the notion that abnormalities in neuroactive steroid secretion are either a cause or an effect of such attacks.

Acute ingestion of MDMA (ecstasy) causes a transient marked increase in serotonin and dopamine at central synapses. Recent studies demonstrated that MDMA induces damage of serotonergic nerve terminals and alters hippocampal processing. Pronounced cognitive deficits in MDMA users affect learning and memory abilities. This pattern of predominant and long-lasting memory dysfunction suggests that the functioning of the hippocampus might be affected by the neurotoxic effects of MDMA. We present the case of a 16-year-old girl who developed an acute organic and psychotic syndrome caused by occasional use of low to moderate dose of MDMA. Serial neuroimaging ((18)F-FDG-PET and brain MRI) were correlated with her neurocognitive performance and clinical evolution. The structural and metabolic changes correlated with a severe cognitive impairment. After 16 months of intensive neuropsychological rehabilitation she showed significant improvement in hippocampal-related memory cognitive functions, which correlated with normalization of her (18)F-FDG-PET and remarkable hippocampal remodelling. This case report indicates that even non-chronic MDMA use may cause subacute toxic encephalopathy in which the clinical evolution is paralleled by neuroimaging changes in specific cerebral areas. The most relevant aspect is the reversibility of the volumetric changes, which may be the structural correlate of an ongoing hippocampal remodelling.

Summary In this paper the chemistry of major and trace elements and, for the first time, strontium isotopic ratios measured in running waters from the Arno River Basin (Tuscany, central-northern Italy) and thermal springs discharging in the same hydrographic system are presented and discussed. Classical graphical methods (e.g. mixing diagrams) have here been improved to identify, in a correct statistical sample space, extreme chemical compositions attributable to the action of geochemical processes and/or inherited from specific lithologies (namely contributions or components 1, 2 and 3) to be used in inverse modeling procedures, due to the absence of clear end-members. A linear least squares problem, with non-negativity constraints and distances, as required for compositional data (convex linear mixing) was solved by considering the contribution of the most discriminant variables given by the 87 Sr/ 86 Sr isotopic ratios and the concentration of Ca 2+ , Mg 2+ , Sr and Rb. Following such approach, it can be assumed ( p 2+ (Mg 2+ )– HCO 3 - radiogenic-rich ( 87 Sr/ 86 Sr = 0.71274; Rb/Sr = 0.039), represents a dominant feature at basin scale, with a weight ranging from 69% to 100%. Much lower percentages are related to component 2, represented by a Ca 2+ (Mg 2+ )– SO 4 2 - facies with intermediate 87 Sr/ 86 Sr (0.70874) and low Rb/Sr (2.8 × 10 −4 ) ratios and component 3, identified by Ca 2+ – HCO 3 - facies with less radiogenic 87 Sr/ 86 Sr (0.70827) and low Mg 2+ /Ca 2+ (0.011) ratios. These components are mainly dominated by the dissolution of evaporitic rocks and/or mixing with thermal waters in the southern part of the Arno River Basin and by dissolution of the carbonatic fraction, kinetically favored with respect to that of the silicatic minerals, in the upper reaches of the main course and its tributaries, respectively.