Neurodegenerative Diseases最新文献

Background: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder caused by a mutation in the ATXN7 gene. The involvement of the brainstem auditory pathway in pathogenesis of this disease has not been systematically assessed.

Aim: To determine involvement of the brainstem auditory pathway in SCA7 patients and its relationship to clinical features of the disease.

Methods: In this case-control study, brainstem auditory-evoked potentials (BAEPs) were assessed in 12 SCA7 patients with clinical and molecular diagnosis, compared to 2 control groups of 16 SCA2 patients and 16 healthy controls.

Results: SCA7 patients exhibited significant prolongation of I-wave and III-wave latencies, whereas SCA2 patients showed increased latencies for III and V waves and I-III interpeak interval. SCA7 patients with larger I-wave latencies exhibited larger CAG repeats, earlier onset age, and higher SARA scores, but in SCA2 cases, these were not observed.

Conclusions: BAEP tests revealed functional involvement of the auditory pathway in SCA7 (mainly at) peripheral portions, which gave new insights into the disease physiopathology different from SCA2 and may unravel distinct pathoanatomical effects of polyQ expansions in the central nervous system.

Significance: These findings offer important insights into the distinctive disease mechanisms in SCA7 and SCA2, which could be useful for differential diagnosis and designing specific precision medicine approaches for both conditions.

Background: Parkinson's disease (PD) patients are known to suffer from subtle cognitive and balance deficits from the early stages although they usually manifest in advanced stages. Postural instability (PI) has been correlated with slower information processing speed. Simple reaction time (SRT) tasks can be used to measure the speed of information processing. The main objective of this study was to examine the usefulness of SRT as a valid predictor of balance in PD, thus providing a simple and complementary assessment method.

Methods: This cross-sectional study included 52 PD patients without dementia who were evaluated for balance using the pull test (PT) maneuver and Biodex® limits of stability (LOS). In addition, a reaction time task was used to measure processing speed. Correlation and linear regression analyses were performed.

Results: The performance of SRT tasks was correlated with the evaluation of LOS% and PT, suggesting that the SRT may be a predictor of balance performance. Longer reaction time and poorer postural stability were also associated with disease duration but not with age.

Conclusions: Poor performance in a simple reaction task can predict altered PI and can complement staging and evaluation in PD patients.

Introduction: Sleep-disordered breathing (SDB) in patients with motor neurone disease (MND) is normally attributed to hypoventilation due to muscle weakness. However, we have observed different patterns of SDB among MND patients referred for non-invasive ventilation, which do not appear to be explained by respiratory muscle weakness alone.

Aim: The aim of this study was to examine the characteristics of SDB in MND.

Methods: This is a retrospective analysis of sleep studies (using polysomnography [PSG]), pulmonary function tests, and arterial blood gases in MND patients referred to a tertiary sleep medicine service for clinical review. Sleep apnoeas were characterised as obstructive or central, and to further characterise the nature of SDB, hypopnoeas were classified as obstructive versus central.

Results: Among 13 MND patients who had a diagnostic PSG, the mean ± SD age was 68.9 ± 9.8 years, BMI 23.0 ± 4.3 kg/m2, forced vital capacity 55.7 ± 20.9% predicted, and partial pressure of CO2 (arterial blood) 52.7 ± 12.1 mm Hg. A total of 38% of patients (5/13) showed evidence of sleep hypoventilation. The total apnoea/hypopnoea index (AHI) was (median [interquartile range]) 44.4(36.2-56.4)/h, with 92% (12/13) showing an AHI >10/h, predominantly due to obstructive events, although 8% (1/13) also showed frequent central apnoea/hypopnoeas.

Conclusions: Patients with MND exhibit a wide variety of SDB. The prevalence of obstructive sleep apnoea (OSA) is surprising considering the normal BMI in most patients. A dystonic tongue and increased upper-airway collapsibility might predispose these patients to OSA. The wide variety of SDB demonstrated might have implications for ventilator settings and patients' outcomes.

Introduction: Although not considered a primary cause, neuroinflammation is associated with many neurodegenerative disorders, including Parkinson's disease (PD).

Methods: To elucidate potential immune involvement in PD, the present study imputed immune cell abundances from bulk RNA-sequencing transcriptomic data of PD postmortem prefrontal cortices. CIBERSORTx, an RNA deconvolution algorithm that implements support vector regression, was used to measure the relative abundances of immune cells from a previously published gene expression dataset. Through this machine-learning approach, relative proportions of 22 immune cell subtypes present in the original brain tissue were estimated.

Results: Prefrontal cortices from PD patients exhibited significantly higher relative abundances of monocytes compared to neuropathologically normal controls (p value = 0.0005). The relative proportions of the other 21 immune subtypes showed no significant differences between control and PD samples.

Conclusion and discussion: The findings corroborate previous reports and suggest monocytes may be involved in PD pathogenesis.

Background: Rivastigmine is an acetylcholine esterase inhibitor which is commonly used as therapy for dementia in Alzheimer's disease and Parkinson's disease (PD). Recently, a randomized controlled trial demonstrated a positive effect of rivastigmine on gait function in nondemented PD patients. Disturbed gait is a shared hallmark of PD and ataxias.

Objectives: We hypothesized that the effect of rivastigmine could be translated to spinocerebellar ataxia (SCA) improving gait function.

Method: Five patients with SCA type 3 were treated with transdermal rivastigmine for 8 weeks. The patients were monitored using the Scale for the Assessment and Rating of Ataxia (SARA) and an electronic walkway system (GAITRite®).

Results: Gait function was not changed by treatment, but 4 patients who continued treatment for 8 weeks showed improved coordination of extremities. The SARA sum score, which was 7.6 ± 2.2 at baseline, had dropped by 1.5 ± 1.9 after 4 weeks and by 2.1 ± 1.4 after 8 weeks.

Conclusions: Contrary to our hypothesis, we observed no improvement of gait parameters as assessed by SARA and GAIT-Rite®, but coordination abilities were improved. Rivastigmine was well tolerated, but known side effects of rivastigmine, such as deterioration of asthma, may appear. Further trials in larger cohorts are needed to confirm our findings.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD.

Objectives: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD.

Methods: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex.

Results: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only.

Conclusions: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.

Background: Parkinson's disease (PD) is characterized by the selective death of dopaminergic neurons in the substantia nigra. Recently, NLRP3 inflammasome and pyroptosis were found to be associated with PD. Cyclosporine A (CsA), an immunosuppressant, reduces neuronal death in PD. However, CsA could hardly pass through the blood-brain barrier (BBB) and high dose is associated with severe side effects and toxicity. N-methyl-4-isoleucine-cyclosporine (NIM811) is a CsA derivate that can pass through the BBB. However, little is known about its effect on PD.

Objective: The objectives of this study were to explore the mechanism of rotenone-induced cell damage and to examine the protective effects of NIM811 on the neurotoxicity of a Parkinson-like in vitro model induced by rotenone.

Methods: Murine hippocampal HT22 cells were cultured with the mitochondrial complex I inhibitor rotenone, a widely used pesticide that has been used for many years as a tool to induce a PD model in vitro and in vivo and proven to be reproducible. NIM811 was added to the culture media 3 h prior to the rotenone incubation. Cell viability was determined by resazurin assay, reactive oxygen species (ROS) production by dihydroethidine (DHE), and mitochondrial membrane potential by tetramethyl rhodamine methyl ester (TMRM). TUNEL and caspase-1 immunofluorescent double staining was used to detect pyroptosis. NLRP3, caspase-1, pro-caspase-1, GSDMD, and interleukin-18 (IL-18) were measured using Western blotting after 24 h of rotenone incubation. The reactivity of interleukin-1β (IL-1β) was determined by ELISA.

Results: Our results demonstrated that rotenone caused more than 40% of cell death, increased ROS production, and reduced mitochondrial membrane potential, while NIM811 reversed these alterations. Immunofluorescent double staining showed that rotenone increased the percentage of caspase-1 and TUNEL double-labelled cells, an indication of pyroptosis, after 24 h of incubation. The protein expression of NLRP3, caspase-1, pro-caspase-1, GSDMD, IL-18, and IL-1β was significantly increased after 24 h of rotenone incubation. NIM811 suppressed rotenone-induced pyroptosis and downregulated the protein expression of NLRP3, caspase-1, pro-caspase-1, GSDMD, IL-1β, and IL-18.

Conclusion: These results provide evidence that rotenone activates the NLRP3 inflammomere and induces pyroptosis. NIM811 protects the cell from rotenone-induced damage and inhibits NLRP3 inflammasome and pyroptosis. NIM811 might serve as a potential therapeutic drug in the treatment of PD.

Background: Currently, the number of individuals who undergo surgery is greatly increased. As a consequence, postoperative cognitive dysfunction (POCD) has gradually gained more attention.

Summary: POCD is a perioperative complication requiring sensitive preoperative and postoperative neuropsychiatric tests, and its incidence in both cardiac and noncardiac surgery is high, especially in elderly individuals. Surgical, patient, and anesthetic factors may all lead to the occurrence and development of POCD. The key mechanism of POCD may be the inflammatory response of the central nervous system during surgery, which is similar to that of Alzheimer's disease (AD). Enriched environment (EE), a factor that can significantly improve and prevent neurodegenerative diseases, may have a beneficial effect on POCD. Key Messages: This review aims to elucidate the mechanism of the occurrence and development of POCD, analyze the possible influence of EE on POCD at the molecular level, and provide a direction for its treatment.

Introduction: Increased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high-resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months of age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data.

Methods: Hemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) maps. VBA on the entire brain was performed using SPM8 and the SPM Mouse toolbox. Initially, all DTI maps were coregistered with the Allen mouse brain atlas to bring them to one common coordinate space. In VBA, coregistered DTI maps were normalized and smoothed in order to perform two-sample and unpaired t tests with false discovery rate correction to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, and hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions of interests were computed with coregistered DTI maps and labels in Allen mouse brain atlas. Afterwards, a Kruskal-Wallis one-way ANOVA on ranks with a Tukey post hoc test was executed on the estimated average values.

Results: With VBA, we found pronounced and brain-wide spread changes when comparing homozygous, P301L mice with non-transgenic littermates, which were not seen when comparing hemizygous P301L with non-transgenic animals. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD, and AD were increased in homozygotes compared to hemizygotes and non-transgenic littermates.

Discussion/conclusion: High-resolution ex vivo DTI demonstrated brain-wide microstructural and gene-dose-dependent changes in the P301L mouse model of human tauopathy. The DTI analysis pipeline may serve for the phenotyping of models of tauopathy and other brain diseases.

Purpose: The present study was designed to investigate the effects of 8-week combined endurance, resistance, and balance exercise training on IL-6, CRP, and IL-10 concentrations in women with multiple sclerosis.

Methods: Thirty participants with multiple sclerosis (Expanded Disability Status Scale ≤6) were randomized into either an exercise and control groups. The exercise group performed 8-weeks of endurance, resistance, and balance exercise training. Serum concentrations of IL-6, CRP, and IL-10 were measured before and after the 8-week intervention. Moreover, anthropometric measures were determined at the onset of and after the intervention. For within- and between groups comparisons of all variables, t test (independent and dependent) was used (p < 0.05).

Results: The results revealed that IL-6 and CRP levels significantly decreased after exercise training (from 6.8 ± 1.52 to 3.2 ± 0.96, p < 0.001 and from 2.76 ± 0.98 to 1.55 ± 0.44, p = <0.001; respectively). Also, exercise training significantly increased IL-10 in the exercise group (from 16.4 ± 2.74 to 23.2 ± 2.11, p < 0.001). There was a significant difference between the 2 groups in all markers in the after 8-week exercise (p < 0.05).

Conclusions: One of the characteristics of MS disease is inflammation. Exercise training through physiological mechanisms and without aggravating the inflammatory pathology can be effective in functional and symptom reduction of patients with MS. In confirmation of this, the present study showed that 8 weeks of combined exercise training decreased pro-inflammatory markers (IL-6 and CRP) and increased anti-inflammatory cytokine (IL-10). Our findings suggested that an exercise training program can be an effective strategy for managing the immune system of women with MS at least by its significant effect on inflammatory markers.