Atrial fibrillation and heart failure have both been suggested to increase stroke and dementia risk. However, in observational studies, reversed causation and unmeasured confounding may occur. To mitigate these issues, this study aims to investigate if higher genetic risk for atrial fibrillation and heart failure increases dementia and stroke risk. Data were obtained from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (N = 984) were born in 1930 with baseline examinations at age 70, 75, 79 or 85 and follow-ups until age 88-89. Polygenic risk scores at the 5 × 10-8, 1 × 10-5, 1 × 10-3 and 1 × 10-1 thresholds were generated for atrial fibrillation and heart failure. Stroke was diagnosed based on self-reports, close-informant interviews, and the National Patient Register. Dementia was diagnosed based on neuropsychiatric examinations, close-informant interviews, and the National Patient Register. Cox regression analyses were performed, adjusted for sex, age at baseline and the first five principal components to correct for population stratification. Those within the highest atrial fibrillation-polygenic risk score tertile had a 1.5 (95% CI 1.09-2.03) increased risk of dementia (at the 1 × 10-5 threshold) and a 1.5 (95% CI 1.07-2.03) increased risk of stroke (at the 1 × 10-3 threshold) compared to the lowest tertile. Those within the highest heart failure-polygenic risk score tertile had a 1.6 (95% CI 1.19-2.27) increased risk of dementia (at the 5 × 10-8 threshold), but no increased risk of stroke (HR 1.2; 95% CI 0.83-1.60 at the 1 × 10-5 threshold), compared to the lowest tertile. When analysing the polygenic risk scores as a continuous variable, the associations were in the same direction, although weaker. This study, investigating genetic risk of atrial fibrillation and heart failure in relation to stroke and dementia, supports the increasing body of evidence suggesting that atrial fibrillation is associated with both stroke and dementia risk. Whether heart failure increases dementia risk is less established, but the present study found that genetic risk of heart failure increased dementia risk. The finding that genetic risk for heart failure did not increase stroke risk needs to be interpreted with caution, as it may be due to a lack of statistical power. There are guidelines on how to best treat atrial fibrillation to prevent stroke, but more knowledge is needed on how to treat atrial fibrillation and heart failure to prevent dementia.
[This retracts the article DOI: 10.1093/braincomms/fcae077.].
Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).
Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 gene have recently been shown to cause spinocerebellar ataxia 27B. Currently, the pathogenic threshold of (GAA)≥300 repeat units is considered highly penetrant, while (GAA)250-299 is likely pathogenic with reduced penetrance. This study investigated the frequency of the GAA repeat expansion and the phenotypic profile in a Cypriot cohort with unresolved late-onset cerebellar ataxia. We analysed this trinucleotide repeat in 155 patients with late-onset cerebellar ataxia and 227 non-neurological disease controls. The repeat locus was examined by long-range PCR followed by fragment analysis using capillary electrophoresis, agarose gel electrophoresis and automated electrophoresis. A comprehensive comparison of all three electrophoresis techniques was conducted. Additionally, bidirectional repeat-primed PCRs and Sanger sequencing were carried out to confirm the absence of any interruptions or non-GAA motifs in the expanded alleles. The (GAA)≥250 repeat expansion was present in 12 (7.7%) patients. The average age at disease onset was 60 ± 13.5 years. The earliest age of onset was observed in a patient with a (GAA)287 repeat expansion, with ataxia symptoms appearing at 25 years of age. All patients with spinocerebellar ataxia 27B displayed symptoms of gait and appendicular ataxia. Nystagmus was observed in 41.7% of the patients, while 58.3% exhibited dysarthria. Our findings indicate that spinocerebellar ataxia 27B represents the predominant aetiology of autosomal dominant cerebellar ataxia in the Cypriot population, as this is the first dominant repeat expansion ataxia type detected in this population. Given our results and existing research, we propose including fibroblast growth factor 14 GAA repeat expansion testing as a first-tier genetic diagnostic approach for patients with late-onset cerebellar ataxia.
Former studies have established that individuals with a cochlear implant (CI) for treating single-sided deafness experience improved speech processing after implantation. However, it is not clear how each ear contributes separately to improve speech perception over time at the behavioural and neural level. In this longitudinal EEG study with four different time points, we measured neural activity in response to various temporally and spectrally degraded spoken words presented monaurally to the CI and non-CI ears (5 left and 5 right ears) in 10 single-sided CI users and 10 age- and sex-matched individuals with normal hearing. Subjective comprehension ratings for each word were also recorded. Data from single-sided CI participants were collected pre-CI implantation, and at 3, 6 and 12 months after implantation. We conducted a time-resolved representational similarity analysis on the EEG data to quantify whether and how neural patterns became more similar to those of normal hearing individuals. At 6 months after implantation, the speech comprehension ratings for the degraded words improved in both ears. Notably, the improvement was more pronounced for the non-CI ears than the CI ears. Furthermore, the enhancement in the non-CI ears was paralleled by increased similarity to neural representational patterns of the normal hearing control group. The maximum of this effect coincided with peak decoding accuracy for spoken-word comprehension (600-1200 ms after stimulus onset). The present data demonstrate that cortical processing gradually normalizes within months after CI implantation for speech presented to the non-CI ear. CI enables the deaf ear to provide afferent input, which, according to our results, complements the input of the non-CI ear, gradually improving its function. These novel findings underscore the feasibility of tracking neural recovery after auditory input restoration using advanced multivariate analysis methods, such as representational similarity analysis.
Visual perceptual learning (VPL), the training-induced improvement in visual tasks, has long been considered the product of neural plasticity at early and local stages of signal processing. However, recent evidence suggests that multiple networks and mechanisms, including stimulus- and task-specific plasticity, concur in generating VPL. Accordingly, early models of VPL, which characterized learning as being local and mostly involving early sensory areas, such as V1, have been updated to embrace these newfound complexities, acknowledging the involvement on parietal (i.e. intra-parietal sulcus) and frontal (i.e. dorsolateral prefrontal cortex) areas, in aspects concerning decision-making, feedback integration and task structure. However, evidence of multiple brain regions differentially involved in different aspects of learning is thus far mostly correlational, emerging from electrophysiological and neuroimaging techniques. To directly address these multiple components of VPL, we propose to use a causal neuromodulation technique, namely transcranial random noise stimulation, to selectively modulate the activity of different brain regions suggested to be involved in various aspects of learning. Specifically, we will target a region in the occipital cortex, which has been associated with stimulus-specific plasticity, and one in the parietal cortex, which has been associated with task-specific plasticity, in a between-subject design. Measures of transfer of learning to untrained stimuli and tasks will be used to evaluate the role of different regions and test for double dissociations between learning effects and stimulated area, shedding lights on learning mechanisms in the visual system. Evidence of dissociable mechanisms of learning can help refine current models of VPL and may help develop more effective visual training and rehabilitation protocols.
Epidemiological evidence associates Toxoplasma gondii latent infection with the development of neuropsychiatric disorders, and various immunological and environmental factors play key pathophysiological roles through host immune response alterations. We investigated the cognitive and motor alterations occurring in the terminal stage of T. gondii infection in rats, and whether a low-protein diet, a high-fat diet or ovariectomy may accelerate their development, given the role of malnutrition and menopause on immunity and resistance to infection. In two sets of experiments, 2-month-old (157.5 ± 4.3 g, n = 42) male (n = 18) and female (n = 24) Wistar rats were infected with T. gondii (ATCC 40050). Open-field and elevated plus maze tests were performed in the terminal stage of infection first and then in the early stage in low-protein diet-fed, high-fat diet-fed and ovariectomized infected rats. Late-stage (90 days) infected and early-stage (17 days) low-protein diet-fed groups showed significant decreases in body weight (42.42%↓, P = 0.016 and 57.14%↓, P < 0.001 versus non-infected, respectively), increases in body temperature (P = 0.001 and P < 0.001, respectively), decreases in blood glucose levels (P = 0.006 and P = 0.020, respectively), signs of cognitive and motor impairment and lower neuron counts. The alterations observed in high-fat diet-fed and ovariectomized infected animals were milder. Low-protein diet feeding to T. gondii-infected rats accelerated the occurrence of the infection terminal stage. Thus, a diet low in proteins could transform a slow early-stage T. gondii infection into an active neurotoxoplasmosis with neuropsychiatric manifestations and possible neurodegeneration in rats.
Accurate and early diagnosis of Alzheimer's disease and vascular dementia is crucial for enabling timely interventions and improving patient outcomes. This study evaluates the diagnostic performance of plasma biomarkers (neurofilament light chain and phosphorylated tau181) and retinal biomarkers (retinal nerve fibre layer and ganglion cell-inner plexiform layer), individually and in combination, in differentiating moderate cognitive impairment and dementia from mild cognitive impairment and no cognitive impairment. A cross-sectional study was conducted involving 509 participants, aged 50 and older, recruited from a memory clinic. The participants were categorized as normal (n = 100), mild cognitive impairment (n = 144), moderate cognitive impairment (n = 90) or dementia (n = 175) based on detailed clinical assessments, neuropsychological testing and MRI scans. The thickness of the ganglion cell-inner plexiform layer (P < 0.001) and retinal nerve fibre layer (P = 0.030) decreased progressively from normal cognition to cognitive impairment and dementia. The thickest layers were observed in individuals with no cognitive impairment (mean ± standard deviation: ganglion cell-inner plexiform layer: 76 ± 11 µm, retinal nerve fibre layer: 92 ± 10 µm), while the thinnest layers were found in individuals with dementia (ganglion cell-inner plexiform layer: 72 ± 14 µm, retinal nerve fibre layer: 89 ± 12 µm). Plasma biomarker levels increased progressively from normal cognition to cognitive impairment and dementia (P < 0.001). Levels were lowest in individuals with no cognitive impairment [median (interquartile range): neurofilament light chain: 15 (9) pg/mL, phosphorylated tau181: 1.85 (1.00) pg/mL] and highest in those with dementia [neurofilament light chain: 34 (27) pg/mL, phosphorylated tau181: 3.24 (2.81) pg/mL]. After adjusting for retinal scan signal strength, neurofilament light chain showed a stronger negative association with retinal nerve fibre layer thickness [standardized beta estimate (β) = -0.184] and ganglion cell-inner plexiform layer thickness (β = -0.139) compared to phosphorylated tau181, which exhibited weaker associations with ganglion cell-inner plexiform layer (β = -0.091) and retinal nerve fibre layer (β = -0.059). While retinal parameters provided modest discriminatory ability (AUC = 0.60), plasma biomarkers demonstrated superior diagnostic performance (AUC = 0.76). Notably, neurofilament light chain had a stronger association with retinal thinning than phosphorylated tau181 and offered superior diagnostic value for identifying moderate cognitive decline. These findings underscore the potential of plasma biomarkers, particularly neurofilament light chain, for the early detection of dementia.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：