Background: Neurotrophins such as brain-derived neurotrophic factor (BDNF), inflammation and oxidative damage may contribute to the pathophysiology of bipolar disorder (BD) in terms of illness activity. To date, there is a lack of studies linking the cognitive impairment observed in BD with these neurobiological mechanisms. This study aimed to investigate the role of these neurobiological factors in clinical and cognitive outcomes in a sample of bipolar individuals.Methods: We measured serum BDNF, cytokines and oxidative stress markers in a sample of 133 individuals: 52 euthymic bipolar patients, 32 manic patients and 49 healthy controls. They were all assessed with a comprehensive cognitive battery. Sociodemographic and clinical data were collected. Multiple linear regression models were built to study associations of neurotrophins and inflammatory and oxidative measures with cognitive functioning.Results: BDNF levels were decreased in euthymic (p = 0.039) and manic (p < 0.001) individuals. Conversely, inflammatory (interleukin 6 (IL-6)) (p = 0.019) and oxidative stress (p = 0.003) measures were increased in bipolar individuals compared to controls. BDNF levels were associated with executive functioning (β = 0.01, p = 0.02) and verbal memory (β = 0.013, p = 0.005), together with other demographic variables. In particular, verbal memory was also associated with obesity (β=-0.04, p = 0.005). Neither inflammatory markers, oxidative stress markers nor other relevant clinical variables showed any association with cognitive outcome.Conclusions: Of all the peripheral neurobiological factors analysed, BDNF was the only one significantly associated with cognitive dysfunction in bipolar disorder individuals. This study emphasizes the role of BDNF not only across mood phases but also in cognitive functioning.

Study Objectives: The majority of studies investigating the association between sleep and Alzheimer’s disease (AD) biomarkers have been performed in healthy participants. Our objective was to investigate the association between sleep and several biomarkers that reflect distinct aspects of AD physiopathology. Methods: The cohort included 104 individuals with mild-moderate AD. The participants were submitted to one-night polysomnography, and cerebrospinal fluid was collected in the following morning to measure the selected biomarkers associated with amyloid deposition, tau pathology, neurodegeneration, axonal damage, synaptic integrity, neuroinflammation, and oxidative damage. Results: There was a positive correlation between neurofilament light (NF-L) and the time spent in stage 1 of non-rapid eyes movement (NREM) (N1) sleep and a negative correlation between this marker and the time spent in stage 3 of NREM (N3) sleep. Accordingly, we observed that deep sleep was associated with lower levels of NF-L, whereas light sleep increased the probability of having higher levels of this marker. Furthermore, chitinase-3-like-1 (YKL-40) was negatively correlated with sleep efficiency, the time spent in stage 2 of NREM (N2) sleep, and the time spent in N3 sleep. Conversely, there was a positive correlation between N3 sleep and the oxidative protein damage markers N-ε-(carboxyethyl)lysine and N-ε-(malondialdehyde)lysine. Conclusions: There were significant correlations between sleep parameters and AD biomarkers related to axonal damage and neuroinflammation, such as NF-L and YKL-40. A lack of deep sleep was associated with higher levels of NF-L. This highlights a potential role for NF-L as a biomarker of sleep disruption in patients with mild-moderate AD in addition to its role in predicting neurodegeneration and cognitive decline.

T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacologic blockers have limited selectivity for TTCC and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cacna1g/Cav3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying short hairpin RNA against Cav3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Cav3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Cav3.1 accompanied by the activation of macroautophagy. We confirmed a positive correlation between Cav3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Cav3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Cav3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy. Significance: These findings identify Cav3.1 calcium channels as a molecular target to regulate autophagy and prevent progression and chemotherapeutic resistance in glioblastoma.

Objective: The aim of this study was to investigate the usefulness of Alzheimer’s disease Cerebrospinal Fluid (CSF) biomarkers in predicting the progression to dementia in patients with Mild Cognitive Impairment (MCI).Methods: One hundred and thirteen patients were consecutively recruited from April 2012 to April 2014. Measurement of CSF biomarkers (amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau)) and a neuropsychological evaluation were performed for all patients. We categorized patients with MCI as A+A- and N+N- based on the presence/absence of amyloid pathology and neurodegeneration, respectively.Results: Of 72 patients with MCI, 26 (36%) progressed to dementia. These patients had lower CSF Aβ42 levels and higher p-tau and t-tau levels at baseline. The proportion that progressed to dementia was 14.3% (2/14), 36.8% (7/19), 66.7% (4/6) and 75% (12/16) in the A-N-, A+N-, A-N+ (SNAP), and A+N+ patients, respectively (p < 0.05). There were significant differences in the probability of progression from amnestic MCI (aMCI) to AD between the A+N+ and A-N- patients (OR = 8.1, 95% CI 1.5-42.3, p = 0.001) but not between SNAP (OR = 7.3, 95% CI 0.9-61, p = 0.02) or A+N- (OR = 2.1, 95% CI 0.4 to 10.4, p = 0.15) patients compared to the A-N- subgroup. None of the biomarker profiles of the subgroups predicted the time until the progression to AD.Conclusion: The use of CSF AD biomarkers in clinical practice improves the certainty of diagnosis and prognosis of patients, especially in patients in the prodromal phase or in patients with atypical presentations.

We compared the clinical and analytical performance of Alzheimer’s disease (AD) plasma biomarkers measured using the single-molecule array (Simoa) and Lumipulse platforms. We quantified the plasma levels of amyloid beta 42 (Aβ42), Aβ40, phosphorylated tau (Ptau181), and total tau biomarkers in 81 patients with mild cognitive impairment (MCI), 30 with AD, and 16 with non-AD dementia. We found a strong correlation between the Simoa and Lumipulse methods. Concerning the clinical diagnosis, Simoa Ptau181/Aβ42 (AUC 0.739, 95% CI 0.592–0.887) and Lumipulse Aβ42 and Ptau181/Aβ42 (AUC 0.735, 95% CI 0.589–0.882 and AUC 0.733, 95% CI 0.567–0.900) had the highest discriminating power. However, their power was significantly lower than that of CSF Aβ42/Aβ40, as measured by Lumipulse (AUC 0.879, 95% CI 0.766–0.992). Simoa Ptau181 and Lumipulse Ptau181/Aβ42 were the markers most consistent with the CSF Aβ42/Aβ40 status (AUC 0.801, 95% CI 0.712–0.890 vs. AUC 0.870, 95% CI 0.806–0.934, respectively) at the ≥2.127 and ≥0.084 cut-offs, respectively. The performance of the Simoa and Lumipulse plasma AD assays is weaker than that of CSF AD biomarkers. At present, the analysed AD plasma biomarkers may be useful for screening to reduce the number of lumbar punctures in the clinical setting.

Understanding of Alzheimer disease is fundamental for early diagnosis and to reduce caregiver burden. The objective of this study is to evaluate the degree of understanding of Alzheimer disease among informal caregivers and different segments of the general population through the Alzheimer's Disease Knowledge Scale. We assessed the knowledge of caregivers in different follow-up periods (less than one year, between 1 and 5 years, and over 5 years since diagnosis) and individuals from the general population. Alzheimer's Disease Knowledge Scale scores were grouped into different items: life impact, risk factors, symptoms, diagnosis, treatment, disease progression, and caregiving. A total of 419 people (215 caregivers and 204 individuals from the general population) were included in the study. No significant differences were found between groups for overall Alzheimer's Disease Knowledge Scale score (19.1 vs. 18.8, P = .9). There is a scarce knowledge of disease risk factors (49.3%) or the care needed (51.2%), while symptoms (78.6%) and course of the disease (77.2%) were the best understood aspects. Older caregiver age was correlated with worse Alzheimer's Disease Knowledge Scale scores overall and for life impact, symptoms, treatment, and disease progression (P < .05). Time since diagnosis improved caregivers' knowledge of Alzheimer disease symptoms (P = .00) and diagnosis (P = .05). Assessing the degree of understanding of Alzheimer disease is essential to the development of health education strategies both in the general population and among caregivers.