Alzheimer's disease with sleep insufficiency: a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier.

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer's disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease.

Antibacterial and Antifungal Sesquiterpenoids: Chemistry, Resource, and Activity.

Infectious diseases caused by bacteria and fungi are threatening human health all over the world. It is an increasingly serious problem that the efficacies of some antibacterial and antifungal agents have been weakened by the drug resistance of some bacteria and fungi, which makes a great need for new antibiotics. Sesquiterpenoids, with abundant structural skeleton types and a wide range of bioactivities, are considered as good candidates to be antibacterial and antifungal agents. In the past decades, many sesquiterpenoids were isolated from plants and fungi that exhibited good antibacterial and antifungal activities. In this review, the names, source, structures, antibacterial and antifungal degrees, and mechanisms of sesquiterpenoids with antibacterial and antifungal activity from 2012 to 2022 are summarized, and the structure-activity relationship of these sesquiterpenoids against bacteria and fungi is also discussed.

Clinical Features and Potential Mechanisms Relating Neuropathological Biomarkers and Blood-Brain Barrier in Patients With Alzheimer's Disease and Hearing Loss.

Background: The aim of this study was to explore clinical features and potential mechanisms relating neuropathological biomarkers and blood-brain barrier (BBB) in Alzheimer's disease (AD) and hearing loss (HL). Materials and Methods: A total of 65 patients with AD were recruited and auditory function was assessed by threshold of pure tone audiometry (PTA). Patients were divided into AD with HL (AD-HL) and AD with no HL (AD-nHL) groups based on the standard of World Health Organization. Clinical symptoms were assessed by multiple rating scales. The levels of neuropathological biomarkers of ß amyloid1-42 (Aß1-42) and multiple phosphorylated tau (P-tau), and BBB factors of matrix metalloproteinases (MMPs), receptor of advanced glycation end products, glial fibrillary acidic protein, and low-density lipoprotein receptor related protein 1 were measured. Results: (1) Compared with AD-nHL group, AD-HL group had significantly impaired overall cognitive function and cognitive domains of memory, language, attention, execution, and activities of daily living (ADL) reflected by the scores of rating scales (P < 0.05). PTA threshold was significantly correlated with the impairments of overall cognitive function and cognitive domains of memory and language, and ADL in patients with AD (P < 0.05). (2) P-tau (S199) level was significantly increased in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD. (3) MMP-3 level was significantly elevated in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD (P < 0.05). (4) In AD-HL group, P-tau (S199) level was significantly and positively correlated with the levels of MMP-2 and MMP-3 in CSF (P < 0.05). Conclusion: AD-HL patients have severely compromised overall cognitive function, multiple cognitive domains, and ADL. The potential mechanisms of AD-HL involve elevations of AD neuropathological biomarker of P-tau (S199) and BBB factor of MMP-3, and close correlations between P-tau (S199) and MMP-2/MMP-3 in CSF. Findings from this investigation highly suggest significance of early evaluation of HL for delaying AD progression, and indicate new directions of drug development by inhibiting neuropathological biomarkers of AD and protecting BBB.

Potential roles of oxidative distress on neurodegeneration in Parkinson's disease with neuropsychiatric symptoms.

Background: Neuropsychiatric symptoms (NPSs) belong to a category of non-motor symptoms of Parkinson's disease (PD), which seriously compromise the quality of life and prognosis of PD. This study focused on the correlations between NPSs, free radicals, neuroinflammatory factors, and neuropathological proteins in cerebrospinal fluid (CSF) in patients with PD, aiming to provide insights into the potential mechanisms and therapeutic target for PD with NPSs (PD-NPSs). Methods: In total, 129 patients with PD were enrolled and assessed by the Neuropsychiatric Symptoms Inventory (NPI); they were divided into the PD-NPSs group (75 patients) and PD with no NPSs (PD-nNPSs) group (54 patients). The levels of hydrogen peroxide (H2O2) and nitric oxide (NO), and hydroxyl radical (·OH), anti-oxidative enzyme, neuroinflammatory factors, and neuropathological proteins in CSF from patients with PD were measured. The levels of the above variables were compared between PD-NPSs and PD-nNPSs groups, and correlation analyses among the above variables were conducted. Results: (1) The levels of H2O2 and NO in CSF from the PD-NPSs group were significantly elevated compared with the PD-nNPSs group (p = 0.001), and NPI score positively correlated with the levels of H2O2 and NO (r = 0.283, P = 0.001; r = 0.231, P = 0.008). Reversely, total superoxide dismutase (tSOD) activity in CSF from the PD-NPSs group was significantly reduced compared with the PD-nNPSs group (p = 0.011), and negatively correlated with NPI score (r = -0.185, p = 0.036). (2) The tumor necrosis factor (TNF)-α level in CSF from the PD-NPSs group was significantly decreased compared with the PD-nNPSs group (p = 0.002) and negatively correlated with NPI score (r = -0.211, p = 0.016). (3) The total tau (T-tau) level in CSF from the PD-NPSs group was significantly higher than in the PD-nNPSs group (p = 0.014) and positively correlated with the NPI score (r = 0.167, p = 0.060). (4) The levels of H2O2 and NO positively correlated with the T-tau level in CSF from the PD-NPSs group (r = 0.183, p = 0.039; r = 0.251, P = 0.004), and the levels of TNF-α and T-tau showed a negative correlation (r = -0.163, p = 0.067). Conclusion: Oxidative distress characterized by the elevations of H2O2 and NO levels may closely correlate with the neurodegeneration in brain regions related to PD-NPSs. Thus, therapeutic antioxidants may become an important target for PD-NPSs therapy.

Olfactory Dysfunction and Its Association With Neuropathologic Proteins in Cerebrospinal Fluid From Patients With Parkinson Disease.

Background and Purpose: Olfactory dysfunction (OD) is a common non-motor symptom of Parkinson disease (PD). However, the relationship between OD and neuropathologic proteins in cerebrospinal fluid (CSF) from PD patients remains unclear. Methods: 166 PD patients were included in the study. Overall olfactory function was assessed by summing up the scores of olfactory threshold, discrimination, and identification by a Sniffin' Sticks test, based on which, patients were divided into PD with OD (PD-OD) and PD with no OD (PD-NOD) groups. CSF samples were obtained from 76 PD patients. The levels of neuropathologic proteins, including α-Synuclein, Aß1-42, total tau (T-tau), and multiple forms of phosphorylated tau (P-tau) in CSF were measured by an enzyme-linked immunosorbent assay. Results: out of the 166 PD patients, 103 cases (62.0%) had OD. The scores of overall olfactory functions, and olfactory threshold, discrimination, and identification in the PD-OD group were all significantly lower than that in the PD-NOD group (P < 0.001). α-Synuclein level in CSF was significantly higher in the PD-OD group than the PD-NOD group (P < 0.05), and was significantly and negatively correlated with the scores of overall olfactory function, and olfactory discrimination and identification (P < 0.05). Aß1-42 level in CSF was higher in the PD-OD group than the PD-NOD group, and was significantly and negatively correlated with the olfactory identification score (P < 0.05). T-tau level in CSF was significantly lower in the PD-OD group than the PD-NOD group (P < 0.05), and was significantly and positively correlated with the olfactory discrimination score (P < 0.05). There was no significant difference in P-tau level in CSF between the PD-OD and PD-NOD groups and no correlation between OD score and P-tau level in CSF. Conclusions: PD-OD includes the impairments of olfactory threshold, discrimination, and identification, and is associated with the significant elevation of α-Synuclein and the decrease of the T-tau level in CSF.

Parkinson's Disease With Depression: The Correlations Between Neuroinflammatory Factors and Neurotransmitters in Cerebrospinal Fluid.

Background: To explore the changes of neuroinflammatory factors in cerebrospinal fluid (CSF) and their correlation with monoamine neurotransmitters in Parkinson's disease (PD) with depression (PD-D) patients. Methods: Neuroinflammatory factors and neurotransmitters in CSF were measured and compared between PD with no depression (PD-ND) and PD-D groups. The relationship between PD-D and neuroinflammatory factors was studied by binary logistic regression equation, and the related factors of PD-D were adjusted. The correlations of the levels of neuroinflammatory factors and neurotransmitters in PD-D group were analyzed. Results: The levels of tumor necrosis factor (TNF)-α in CSF from PD-D group were significantly higher and there were no significant differences in the levels of interleukin-1ß, prostaglandin (PG) E2, hydrogen peroxide (H2O2), and nitric oxide (NO). The 24-item Hamilton Depression Scale (HAMD-24) score was positively correlated with the level of TNF-α in CSF. Binary logistic regression showed that the OR of CSF TNF-α level was 1.035 (95% CI 1.002-1.069). The level of dopamine (DA) in CSF of PD-D group was significantly lower than that in PD-ND group. TNF-α level was negatively correlated with DA level in CSF from PD patients (r = -0.320, P = 0.003). Conclusions: Neuroinflammatory factors, especially TNF-α, may play an important role in PD-D. It may cause damage to DA neurons and lead to the depletion of DA, which is related to the occurrence and development of PD-D.

The Relationship Between Retinal Nerve Fiber Layer Thickness and Clinical Symptoms of Alzheimer's Disease.

Background/Aim: Retinal nerve fiber layer (RNFL) thickness (RT), which can reflect the status of the retinal optic nerve cells, may be affected in patients with Alzheimer's disease (AD). There are few studies on the correlation of RT of patients with AD (AD-RT) with clinical symptoms of various cognitive domains, neuropsychiatric symptoms, and activities of daily living (ADL). This study is to investigate the relationships between RT and the abovementioned clinical symptoms of AD. Methods: A total of 96 patients with AD were included in this study. RT was measured in these patients using optical coherence tomography (OCT). Demographic variables, RT, and clinical symptoms were compared between the normal and the abnormal AD-RT groups. Clinical symptoms, including cognitive symptoms, neuropsychiatric symptoms, and ADL, were evaluated using a series of rating scales. Results: The relationships between RT and cognitive symptoms scores were analyzed in patients with AD. Reduced RT was found in 54.4% of patients with AD. The average RT, RT of the superior 1/2 quadrant, and RT of the inferior 1/2 quadrant of both eyes were all significantly decreased in the abnormal AD-RT group (p < 0.001). Overall cognitive function and performance in multiple cognitive domains, including memory, language, attention, and executive function, were also significantly impaired in the abnormal AD-RT group (p < 0.05). For lower RT value, the global cognitive function and the performance in multiple cognitive domains were worse. ADL was significantly compromised in patients with AD having lower RT values (p < 0.05). Conclusions: Lower RT value appear to be correlated with cognitive impairment, and RT may be an indicator of cognitive decline in patients with AD. Further studies are required to confirm our findings.